ArticlePDF AvailableLiterature Review

Copper‐based nanomaterials for cancer theranostics

April 2022
Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 14(4)

April 2022
14(4)

DOI:10.1002/wnan.1797

Authors:

Xiaoyan Zhong

Soochow University (PRC)

Xingliang Dai

Anhui Medical University

Show all 6 authorsHide

Copper‐based nanomaterials (Cu‐based NMs) with favorable biocompatibility and unique properties have attracted the attention of many biomedical researchers. Cu‐based NMs are one of the most widely studied materials in cancer treatment. In recent years, great progress has been made in the field of biomedicine, especially in the treatment and diagnosis of tumors. This review begins with the classification of Cu‐based NMs and the recent synthetic strategies of Cu‐based NMs. Then, according to the abundant and special properties of Cu‐based NMs, their application in biomedicine is summarized in detail. For biomedical imaging, such as photoacoustic imaging, positron emission tomography imaging, and multimodal imaging based on Cu‐based NMs are summarized, as well as strategies to improve the diagnostic effectiveness. Moreover, a series of unique structures and functions as well as the underlying property activity relationship of Cu‐based NMs were shown to highlight their promising therapeutic performance. Cu‐based NMs have been widely used in monotherapies, such as photothermal therapy (PTT) and chemodynamic therapy (CDT). Moreover, the sophisticated design in composition, structure, and surface fabrication of Cu‐based NMs can endow these NMs with more modalities in cancer diagnosis and therapy. To further improve the efficiency of cancer treatment, combined therapy based on Cu‐based NMs was introduced in detail. Finally, the challenges, critical factors, and future prospects for the clinical translation of Cu‐based NMs as multifunctional theranostic agents were also considered and discussed. The aim of this review is to provide a better understanding and key consideration for the rational design of this increasingly important new paradigm of Cu‐based NMs as theranostic agents. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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ADVANCED REVIEW

Copper-based nanomaterials for cancer theranostics

Xiaoyan Zhong

| Xingliang Dai

| Yan Wang

| Hua Wang

Haisheng Qian

| Xianwen Wang

School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of

Soochow University, Suzhou, China

Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China

Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, Hefei, China

Correspondence

Xianwen Wang, School of Biomedical

Engineering, Research and Engineering

Center of Biomedical Materials, Anhui

Medical University, Hefei 230032, China.

Email: xianwenwang@ahmu.edu.cn

Funding information

The Basic and Clinical Cooperative

Research and Promotion Program of

Anhui Medical University, Grant/Award

Number: 2021xkjT028; Jiangsu Natural

Science Fund for Young Scholars, Grant/

Award Number: BK20210730; Grants for

Scientific Research of BSKY from Anhui

Medical University, Grant/Award

Number: 1406012201; The Open Fund of

Key Laboratory of Antiinflammatory and

Immune Medicine, Grant/Award Number:

KFJJ-2021-11; The Postdoctoral Science

Foundation of China, Grant/Award

Number: 2021M702383

Edited by: Gareth Williams, Associate

Editor and Gregory M Lanza, Co-Editor-

in-Chief

Abstract

Copper-based nanomaterials (Cu-based NMs) with favorable biocompatibility

and unique properties have attracted the attention of many biomedical

researchers. Cu-based NMs are one of the most widely studied materials in

cancer treatment. In recent years, great progress has been made in the field of

biomedicine, especially in the treatment and diagnosis of tumors. This review

begins with the classification of Cu-based NMs and the recent synthetic strate-

gies of Cu-based NMs. Then, according to the abundant and special properties

of Cu-based NMs, their application in biomedicine is summarized in detail.

For biomedical imaging, such as photoacoustic imaging, positron emission

tomography imaging, and multimodal imaging based on Cu-based NMs are

summarized, as well as strategies to improve the diagnostic effectiveness.

Moreover, a series of unique structures and functions as well as the underlying

property activity relationship of Cu-based NMs were shown to highlight their

promising therapeutic performance. Cu-based NMs have been widely used in

monotherapies, such as photothermal therapy (PTT) and chemodynamic ther-

apy (CDT). Moreover, the sophisticated design in composition, structure, and

surface fabrication of Cu-based NMs can endow these NMs with more modali-

ties in cancer diagnosis and therapy. To further improve the efficiency of can-

cer treatment, combined therapy based on Cu-based NMs was introduced in

detail. Finally, the challenges, critical factors, and future prospects for the clini-

cal translation of Cu-based NMs as multifunctional theranostic agents were

also considered and discussed. The aim of this review is to provide a better

understanding and key consideration for the rational design of this increas-

ingly important new paradigm of Cu-based NMs as theranostic agents.

Xiaoyan Zhong and Xingliang Dai contributed equally to this study.

Received: 31 January 2022 Revised: 14 March 2022 Accepted: 15 March 2022

DOI: 10.1002/wnan.1797

https://doi.org/10.1002/wnan.1797

This article is categorized under:

Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic

Disease

Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

KEYWORDS

cancer imaging, cancer therapy, combination therapy, Cu-based NMs, tumor

microenvironment

1|INTRODUCTION

In recent decades, the emergence of modern therapeutic nanomedicine has aroused intensive research interest in the

scientific community to explore and develop multifunctional biomaterial nanosystems to meet the stringent requirements

of clinical medicine (Wang, Xu, et al., 2021; Wang, Zhong, et al., 2021; Zhuang et al., 2022). This interdisciplinary field

has also facilitated the development of novel therapeutic modalities against a variety of diseases, in which the rapid devel-

opment of nanomaterials is the fundamental/critical basis and prerequisite for determining the ultimate therapeutic effect

(Dong, Feng, Xu, et al., 2020; Yang et al., 2020). Organic nanomaterials have been extensively explored in nanomedicine,

with clinically relevant family members entering the clinical stage. In contrast, inorganic nanomaterials have been

primarily created in the past decade, with remarkable progress in recent years. These inorganic nanoplatforms possess

inherent electronic, photonic, acoustic, and magnetic properties not possessed by conventional organic nanosystems (Ren

et al., 2021; Ruan & Qian, 2021). Among them, copper-based nanomaterials (Cu-based NMs) are the most representative

example in the field of nanomedicine and have attracted extensive attention, mainly due to their unique physicochemical

properties and excellent biocompatibility. In addition, compared with other nanomaterials, Cu-based nanomaterials are

easier to control and tune the structure, composition, morphology, and size during the preparation process, which pro-

vides more opportunities for their different biomedical applications (Liu, Liu, et al., 2020).

There are many different types of Cu-based NMs, mainly including copper oxides (e.g., Cu

O, CuO), copper sulfides

(e.g., Cu

S, CuS, Cu

), copper selenides (e.g., Cu

Se, CuSe, Cu

2x

Se), copper tellurides (e.g., Cu

Te, CuTe, Cu

2x

Te),

copper coordination compounds (e.g., Cu-tannic acid), and copper-based nanocomposites (e.g., Fe

@Cu

2x

S, Au-

). The synthesis strategies of Cu-based NMs are diversified and mainly include solvothermal/hydrothermal

methods, high-temperature thermal decomposition methods, colloidal synthesis methods, microwave-assisted synthetic

methods, cationic exchange methods, and template-oriented synthesis methods (Wu et al., 2022; Yun et al., 2020). Cu-

based NMs have many types and categories, simple preparation, diversified morphology and functions, which make

them play an increasingly powerful role in tumor imaging and therapy (Wang, Ma, et al., 2017; Wang, Shi, et al., 2021).

Using biocompatible molecules and polymers to simply modify the surface of Cu-based NMs can significantly improve

their pharmacokinetic parameters, thereby improving their colloidal stability, reducing toxicity, and prolonging the

blood circulation time (Zhang, Zeng, & Li, 2020). The unique physicochemical properties of Cu-based NMs enable them

to have various applications in tumor imaging and treatment, which are mainly divided into the following aspects:

(1) Cu-based NMs have good near-infrared (NIR) absorption and excellent photothermal performance, which have been

widely used in photothermal therapy (PTT) and photoacoustic (PA) imaging of tumors; (2) Cu-based NMs have rela-

tively large specific surface areas and can be used to load different chemotherapeutic drugs for tumor chemotherapy;

(3) Cu-based NMs can be used as excellent Fenton-like reagents to generate a large number of hydroxyl radicals (OH)

in the presence of H

, which can be used for chemodynamic therapy (CDT) of tumors; (4) Cu-based NMs are also

often used as photosensitizers to produce a large amount of reactive oxygen species (ROS) under light irradiation,

which can be used for photodynamic therapy (PDT) of tumors. In addition, to endow Cu-based NMs with more func-

tions, Cu-based nanocomposites with excellent properties were successfully constructed to realize the combined treat-

ment of tumors (Zhou et al., 2016).

Cu-based NMs have become one of the research hotspots in the field of cancer theranostics due to their unique

physical and chemical properties (Gilam et al., 2016; Goel et al., 2018). Over the past 5 years, more than 15,000 peer-

reviewed copper-based nanomaterials have been reported for cancer treatment and imaging. However, there are only a

few reviews on the application of copper-based NMs in cancer therapy, which are limited to copper sulfide, and there is

2of43 ZHONG ET AL.

a lack of a systematic summary of Cu-based NMs (Dong, Feng, Xu, et al., 2020; Goel et al., 2014; Liu, Liu, et al., 2020;

Yun et al., 2020; Zhang, Zeng, & Li, 2020; Zhou et al., 2016). In recent years, many new cancer therapies based on Cu-

based NMs, such as CDT, radiodynamic therapy (RDT), immunotherapy, and sonodynamic therapy (SDT), have begun

to emerge. In addition, Cu-based NMs have also been reported to regulate the tumor microenvironment (TME) to

enhance cancer treatment (Hao, Zhang, et al., 2021). Therefore, it is urgent and necessary to systematically summarize

the recent progress of Cu-based NMs in cancer treatment. Herein, this review introduces the application progress of

Cu-based NMs in cancer theranostics in detail (Scheme 1). For cancer imaging, PA imaging, positron emission tomogra-

phy (PET) imaging, and multimodal imaging based on Cu-based NMs were summarized, as well as strategies to

improve the diagnostic effectiveness. Next, the application of Cu-based NMs in tumor treatment was introduced, which

was mainly divided into monotherapy and combination therapy. Cu-based NMs have been extensively used in

monotherapy, such as PTT and CDT. To further improve the efficiency of cancer treatment, combined therapy based

on Cu-based NMs was introduced in detail. Finally, the challenges, critical factors, and future prospects for the clinical

translation of Cu-based NMs as multifunctional theranostic agents were also considered and discussed. The aim of this

review is to provide a better understanding and key consideration for the rational design of this increasingly important

new paradigm of Cu-based NMs as theranostic agents.

2|Cu-BASED NMs USED FOR CANCER IMAGING

Cancer imaging provides important evidence for the diagnosis of cancer via different modalities. However, limited to

the lack of sensitivity toward contrast agents (CAs), the lack of specificity to tumors, and the insufficient accumulation

of CAs in the target sites, nanomaterial-based CAs allow us to precisely obtain anatomical information to determine

the stage of cancer (Siddique & Chow, 2020). Cu-based NMs have been applied as multifunctional CAs in many kinds

of imaging modalities. Below, we introduce Cu-based CAs in unimodal and multimodal imaging of cancer (Table 1).

SCHEME 1 Cu-based NMs for cancer theranostics. Reprinted with permission from Cui et al. (2018). American Chemical Society, 2018.

ZHONG ET AL.3of43

TABLE 1 Cu-based NMs in cancer imaging

Classification Imaging modality Cu-based NMs Parameters References

Single mode

imaging

FL imaging PGC-DOX DOX/IR800 labeling Fu et al. (2021)

Ce6-DNA-zyme/[Cu

(tz)]

Cy5 labeling Liu, Xu, Yang,

et al. (2021)

UCCG UCNP Wang, Chang,

et al. (2021)

IR thermal imaging Cu

2x

Se@FCS 1064-nm laser (1.5 W cm

2

10 min)

Zhang, Li,

et al. (2021)

5-FU/Cu-LDH@nAb-

PTX

808-nm laser (0.75 W cm

2

3 min)

Liu, Liu, Zhang,

et al. (2021)

AuNRs-CTN@THA 808-nm laser (1 W cm

2

2 min)

Gao et al. (2020)

Cu-DhaTph 808-nm laser (1.5 W cm

2

10 min)

Feng et al. (2021)

O@CaCO

1064-nm laser (0.5 W cm

2

) Chang et al. (2020)

PA imaging CuS@GNPs 980-nm laser (0.8 W cm

2

10 min)

Zhang, Xie,

et al. (2021)

Fe-Cu@PANI 808-nm laser

(1.5 W cm

2

, 5 min)

Wang, Zhang,

et al. (2021)

Cu(DTC)

[Cu] =5mgkg

1

Pan et al. (2021)

SPECT imaging [

Cu]Cu-NOTA-

Pertuzumab

3.7 or 7.4 MBq Hao, Mastren,

et al. (2021)

PET imaging [

Cu]CuInS/ZnS 150 μCi in vitro

300 μCi in vivo

Guo et al. (2015)

-weighted MR imaging M-CSTD.NHAc/Cu(II) [Cu] =8 mM Song et al. (2021)

CuS 16 mg Cu kg

1

Dong et al. (2019)

Cu-TG Yuan et al. (2020)

Multimodal

imaging

FL–PA imaging PDC/P@HCuS 680- to 980-nm

Cy7.5-labeling

Sun et al. (2019)

AIBA@FeCuS-FeCO Cy5.5-labeling Sun, An, et al. (2021)

PA–CT imaging T80-AuPt@CuS 808-nm laser

175 μA, 65 kV

Cai et al. (2021)

IR thermal–FL imaging DSF@PVP/Cu-HMPB FITC-labeling Wu et al. (2020)

PT-V@TPDOX DOX delivering Sun, An, et al. (2021)

TPP-ZC-IR-PNPs IR780 delivering

808-nm laser

(1 W cm

2

, 5 min)

Ruttala et al. (2021)

FA-CD@PP-CpG 808-nm laser (0.987 W cm

2

)

PpIX delivering

Chen, Zhou,

et al. (2019)

UCCZ-FA 980-nm laser (1.0 W cm

2

)

Cy5 labeling

Zhang, Sun,

et al. (2020)

IR thermal–BL imaging CF 1064-nm laser (1.5 W cm

2

)

luciferase-T24 cells

Zhang, Li,

et al. (2021)

IR thermal–PA imaging BP-CuS-FA 808-nm laser (1.0 W cm

2

) Jana et al. (2020)

CuFe

808-nm laser (1 W cm

2

5 min)

Liu, Liu, Wan,

et al. (2021)

808-nm laser (0.5 W cm

2

) Chang et al. (2020)

4of43 ZHONG ET AL.

2.1 |Cu-based NMs used for cancer unimodal imaging

Cu-based NMs as the CAs have been successfully prepared for use in fluorescence (FL) imaging, PA imaging, magnetic

resonance (MR) imaging, positron emission tomography (PET) imaging, and computed tomography (CT) imaging in

cancer unimodal imaging.

Aberrant expression of miRNAs is highly related to the development, progression, and metastasis of cancer. To

directly image low-abundance intracellular miRNAs in vivo for monitoring the pathological condition of cancers, a self-

powered DNA@Cu-MOF nanosystem was prepared for TME hypoxia-responsive in vivo temporal–spatial fluorescence

TABLE 1 (Continued)

Classification Imaging modality Cu-based NMs Parameters References

Se 1064-nm laser (0.75 or

1.0 W cm

2

)

Wang, Zhong,

et al. (2019)

PCPT 808-nm laser (1.0 W cm

2

7 min)

Liang et al. (2019)

RGD-CuS DENPs/

pDNA

1064-nm laser (0.6 W cm

2

5 min)

[Cu] =12 mM

Ouyang et al. (2021)

IR thermal–CT imaging Cu

2x

S:Pt(0.3)/PVP 200 μl, 8.5 mg Cu kg

1

Dong et al. (2018)

IR thermal–T

-MR imaging Cu@Gd

808-nm laser (0.8 W cm

2

) Liu, Xu, Yang,

et al. (2021)

IR thermal–PET imaging BP@Cu

0.4

@PEG-RGD 808-nm laser (1.0 W cm

2

2 min)

Cu labeling (74 MBq μg

1

)

Lyu et al. (2020)

IR thermal–X-ray imaging Cu

BiS

800-nm laser (1.726 W cm

2

) Veeranarayanan

et al. (2018)

IR thermal–T

-weighted MR–

FL imaging

MCIH 808-nm laser (0.76 W cm

2

7 min)

ICG delivering

Sun et al. (2020)

IR thermal–T

-weighted MR–

FL imaging

BSA-CuFeS

808-nm laser (1.5 W cm

2

)

DiR-labeling

Chen, Luo,

et al. (2019)

IR thermal–FL–PA imaging Ag

2x

S 635-nm laser (0.40 W cm

2

15 min)

Zhao et al. (2020)

PhA@NanoICG 808-nm laser (1.0 W cm

2

)

ICG delivering

Chen, Zuo,

et al. (2021)

IR thermal–PA-γimaging CuS/

131

I-PEGDA/

AIPH

915-nm laser (1.0 W cm

2

)

131

I-labeling (50 μCi)

Meng et al. (2018)

IR thermal–FL–BL imaging AM@DLMSN@CuS/

R848

980-nm laser (1.0 W cm

2

)

IR780 labeling (100 μgkg

1

)

Luciferase-4 T1 cells

Cheng et al. (2020)

IR thermal–CT–PA imaging CaO

-Cu/ICG@PCM 808-nm laser (1.02 W cm

2

9 min)

Sun, Bin, et al. (2021)

FL–PET–PA imaging NCP Cy5.5-labeling

Zr-labeling (200 μCi)

IR780 labeling (30 μg)

Deng et al. (2022)

FL–CT–PA imaging PtCu

Cy5.5 labeling Zhong et al. (2020)

FL–CT–PET imaging Cu(II)NS TCPP delivering

Cu (1000 μCi)

Wang et al. (2022)

IR thermal–PA–FL–SPECT/CT

imaging

99m

Tc-M-CuS-PEG 1064-nm laser (0.5 W cm

2

)

Cy5.5 labeling

99m

Tc (800 μCi)

Yi et al. (2021)

ZHONG ET AL.5of43

FIGURE 1 Cu-based NMs for cancer single mode imaging. (a) DNA@Cu-MOF nanosystem for FL imaging of human breast cancer.

Chemistry. (d) [64Cu]CuS-PEG-c(RGDfK) NPs for PET imaging of glioma. Reprinted with permission from Cui et al. (2018). American

Chemical Society, 2018. (e) Cu

2x

S:Pt(0.3)/PVP NPs for CT imaging of breast cancer. Reprinted with permission from Dong et al. (2018). The

Royal Society of Chemistry, 2018

6of43 ZHONG ET AL.

imaging of aberrant miRNAs and hypoxic tumors (Figure 1a; Meng et al., 2020). In this design, upon entering hypoxic

tumors, the DNA@Cu-MOF nanosystem could spontaneously degrade and release Cy3-labeled DNAzyme precursor,

Cy5.5/FAM-labeled Cu-Sub, and Cu

ions. Originally, Cy3 fluorescence was blocked in the DNAzyme precursor; how-

ever, in the presence of miRNA-21, the signal strand was replaced through toehold-mediated strand displacement

hybridization, which resulted in the fluorescence recovery of Cy3, achieving the specific detection of anomalously

expressed miRNAs in vivo. In addition, this displacement procedure also induced the exposure of the recognition site of

Cu-Sub for Cu

-catalyzed Cu-Sub cleavage processes, leading to the recovery of aberrant miRNA expression-

dependent Cy5.5 fluorescence for hypoxic tumor diagnosis.

PA imaging, as another noninvasive modality, has been rapidly developed with superb contrast, spatial resolution,

high penetrability, and sensitivity to tissue (Fu et al., 2019). In recent years, a series of PA-imaging CAs have been

developed to improve imaging performance in biomedical applications. For example, biodegradable layered double

hydroxide (LDH)-copper sulfide (CuS) nanocomposites were successfully prepared for PA imaging of breast cancer

(Figure 1b; Liu, Tang, et al., 2020). Due to the high photothermal conversion efficiency, LDH-CuS NCs not only worked

as CAs for PA imaging but also as photothermal agents for PTT under 808-nm laser irradiation. In addition, the hetero-

junction was helpful for the separation of electron (e



) and hole (h

), making LDH-CuS NCs good photodynamic

agents for superoxide anion (

) generation. Moreover, the Cu

in the CuS dots could react with H

to generate

OH for CDT. Overall, LDH-CuS NCs mediated PA imaging-guided PTT-PDT-CDT of cancer via NIR-triggered lyso-

some pathway death.

MR imaging, unlike functional imaging modalities such as FL and PA imaging, is a kind of structural imaging with

high image resolution for soft tissues, and it has been widely used clinically. The principle of MR imaging is the process

of aligning and relaxing hydrogen protons under an external magnetic field. The ability of magnetic nanoparticles

(MNPs) enhances the proton relaxation of specific tissues (Sun et al., 2008). In addition to Fe-, Mn-, and Gd-based

MNPs, Cu

ions were also reported to be good CAs for MR imaging. For example, highly active (102) surface-abundant

CuS NCs could be used to conduct pH and NIR light-responsive T

-weighted MR imaging of breast cancer (Figure 1c;

Dong et al., 2019). In detail, the high Cu vacancies endowed CuS NCs with a small bandgap for high photothermal con-

version efficiency (46%). Accompanied by the negative formation energy of S vacancies, the (102) surface could be

quickly degraded by pH and 808-nm laser irradiation. The intrinsic high absorbance of CuS NCs could mediate the PTT

of cancer. Then, a large amount of Cu

ions were released from CuS NCs to produce high concentrations of superoxide

anion (O



) and OH for PDT under 808-nm laser irradiation. Meanwhile, the oxidation of Cu

ions into Cu

ions

could be applied for in situ T

-weighted MR imaging (MRI), realizing MRI-guided PTT and PDT of cancer.

Cu, a radioactive form of Cu, can emit β-ray for PET imaging of cancer. In addition,

Cu could be used to build

CuS NPs with no need for a radiometal chelator. Herein,

Cu-labeled CuS-PEG nanoparticles with target-directed

c(RGDFK) were prepared via click-chemistry-assisted synthesis for PET imaging of U87 xenograft tumors (Figure 1d;

Cui et al., 2018).

In addition to MR imaging, CT imaging also belongs to the structural imaging modality and is widely used for diag-

nosis. It has high spatial and temporal resolution and can provide precise three-dimensional (3D) anatomical informa-

tion of specific tissues. However, it also lacks sensitivity toward CAs, especially for light metal-based NMs. Fortunately,

heavy elements have unique X-ray attenuation properties for enhanced CT images. By incorporating Cu and Pt ele-

ments, Cu

2x

S:Pt(0.3)/PVP NPs were simply constructed for CT imaging of breast cancer (Figure 1e; Dong et al., 2018).

In this work, Pt ions not only functioned as CAs for CT imaging but could also realize chemotherapy by Pt

ions from

GSH-reduced Pt

ions. Combined with the high absorbance within the NIR region, Cu

2x

S:Pt(0.3)/PVP NPs could also

work for PTT under 808-nm laser irradiation.

2.2 |Cu-based NMs used for cancer multimodal imaging

As mentioned above, each imaging modality has its merits and demerits in providing structural and functional informa-

tion. To learn from each other, a multimodal imaging modality is more reasonable and acceptable to offer comprehen-

sive information of the diseases. For instance, to precisely diagnose lymph node metastasis, CuS NPs were labeled with

fluorescent Cy5.5 for α

targeted and noninvasive dual modal FL-CT imaging of metastatic gastric cancer cells in

lymph nodes (Figure 2a; Shi et al., 2018). RGD-CuS-Cy5.5 NPs could readily drain into sentinel lymph nodes (SLNs) to

target MNK45 gastric tumor cells via the interaction between RGD and α

, offering strong fluorescence at 695 nm for

FL imaging and remarkable CT contrast indicative of SLN metastasis. This work combined functional and structural

ZHONG ET AL.7of43

imaging modalities to provide more information on metastatic gastric cancer. In another study, simultaneous

tetramodal imaging, including PET/FL/Cerenkov luminescence (CL)/Cerenkov radiation energy transfer (CRET) imag-

ing, was simply realized by [

Zr]CSNC for rapid and accurate delineation of breast tumors (Figure 2b; Goel

et al., 2018). [

Zr]CSNC nanoconstructs were prepared by

Zr-labeled hollow mesoporous silica nanoshells (HMSN)

FIGURE 2 Cu-based NMs for cancer multimodal imaging. (a) CuS NPs for dual modal FL-CT imaging of human gastric cancer.

Reprinted with permission from Shi et al. (2018). Elsevier Ltd., 2018. (b) CSNCs for four modal FL-CL-PET-CRET imaging of breast cancer.

Reprinted with permission from Goel et al. (2018). WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2017

8of43 ZHONG ET AL.

filled with CuS NPs and meso-tetrakis(4-carboxyphenyl)porphyrin (TCPP) via an electrostatic interaction-driven self-

assembly method. In these nanoconstructs, zirconium-89 (

Zr) was used for PET and Cerenkov luminescence

(CL) imaging. TCPP worked not only for FL imaging but also as a photosensitizer for

generation. Interestingly,

CRET could occur between the fluorescent TCPP and radioactively decayed

Zr, achieving another diminished

autofluorescence imaging of cancer with improved tumor-to-background contrast.

3|Cu-BASED NMs FOR CANCER MONOTHERAPY

Among the transition-metal-based NMs, the copper age of Cu-involved cancer theranostics has arrived. As an essential

element that participates in biological processes, including angiogenesis and lipid/glucose metabolism, Cu-based NMs

with intriguing theranostic performance have motivated scientists to apply them to the field of cancer (Meng

et al., 2020). In addition to the multimodal imaging properties of Cu-based NMs in visualizing tumors, these NMs have

also shown promise in cancer therapy owing to their unique structures and functions with various physicochemical

properties and bioactivities (Meng et al., 2020). At present, Cu-based cancer monotherapy includes external stimuli

such as light triggered PTT and PDT, ultrasound (US) excited SDT, X-ray initiated RDT, and internal chemical energy-

driven CDT (Table 2; Zhong et al., 2021).

3.1 |Photothermal therapy

The beneficial effect of heat in resisting cancer was first observed in the 19th century owing to fever caused by bacterial

infection. In particular, PTT, which uses NMs capable of generating efficient heat under laser irradiation to achieve

tumor ablation, has become attractive for the last few decades (Jaque et al., 2014). Tremendous efforts have been made

toward improving PTT performance. To date, numerous functional NMs have been reported to be efficient

photothermal transduction agents (PTAs) for PTT, such as metal-based, carbon-based, organic nanoparticle, polymer-

based, and hybrid NMs (Kumari et al., 2021; Zhou et al., 2020; Zhou, Wang, et al., 2021). However, Cu-based PTAs

show advantages in relatively high photothermal conversion efficiency (PCE), thermostability, catalytic performance,

and others. For example, amorphous Ag

2x

S quantum dots (QDs) were characterized with good photothermal/PA

properties, showing a high photothermal conversion efficiency of 44.0% (Figure 3a; Zhao et al., 2020). With the lowest

absorbance within the first biowindow (820 nm), Ag

2x

S QDs could realize infrared (IR) and PA imaging-guided

PTT under a relatively low-power irradiation of a 635-nm laser (0.8 W cm

2

) and demonstrated no long-term toxicity.

Despite the success of diodes as excited light in PTT, the strong extinction coefficients of human tissues within the

visible region limit diode-excited PTT in superficial tumors. Therefore, longer-wavelength NIR light that is adjusted to

the tissue-transparent windows of both the first window (750–1000 nm; NIR-I) and second window (1000–1350 nm;

NIR-II) can penetrate much deeper body tissues (Liu et al., 2019). For this purpose, many types of Cu-involved PTAs

that are responsive to NIR light have been made for PTT. For example, CuS nanocrystals (NCs) were grafted onto the

surface of gelatin nanoparticles (GNPs), forming transformable CuS@GNP structures for the thermal ablation of

human MDA-MB-23 tumors (Figure 3b; Li et al., 2021). Although this nanostructure was approximately 120 nm in

diameter and hardly penetrated into the central zone of the tumor, the overexpressed hydrolases rapidly dissociated the

scaffold to release tiny CuS NCs (8.00 ± 1.46 nm) to efficiently mediate deep PTT of the inner tumor via enzyme-

induced multistage delivery under an NIR laser (980 nm, 0.8 W cm

2

) irradiation. The photothermal conversion effi-

ciency was calculated to be only 10.84%; however, this was fairly efficient for photothermal ablation both in vitro and

in vivo.

In addition to the high concentration of enzymes in the TME, glutathione (GSH) is also highly produced by tumor

cells to maintain redox balance, which is approximately 1000 times higher than that of healthy cells (Yin et al., 2018).

Therefore, GSH can function as another endogenous stimulator to activate tumor-specific therapy. Iron-copper codoped

polyaniline (Fe-Cu@PANI) NPs were prepared to act as GSH-induced absorption spectrum redshift PTAs, from the visi-

ble to NIR region, for PTT of 4T1 breast cancer (Figure 3c; Wang, Zhang, et al., 2021). In this architecture, the Cu

ions were first reduced by GSH, thus depleting GSH, followed by the production of protonated PANI with a maximum

absorption redshifted from 615 to 820 nm. In addition, the higher the concentration of GSH was, the higher the

absorbance at 820 nm, making protonated PANI with ultrahigh photothermal conversion stability even after 6 cycles of

808-nm laser irradiation at a power density of 1.5 W cm

2

. For the assessment of the anticancer effect, Fe-Cu@PANI

ZHONG ET AL.9of43

under laser irradiation could destroy 4T1 cells in vitro and effectively inhibit the growth of tumors in vivo. Moreover,

histopathological analysis further indicated the biosafety of this PTA at the selective dose.

To successfully display the high tissue penetration ability of NIR light, an orthotopic bladder cancer (BCa) model

was used in efficient NIR-II PTT. For the treatment of BCa, the traditional therapeutic option in the clinic is intravesical

instillation. However, this method has limited efficacy because the residence time and transmucosal performance of

therapeutic agents are greatly restricted. To overcome these limitations, fluorinated chitosan (FCS)-modified Cu

2x

(Cu

2x

Se@FCS, denoted CF) NPs were fabricated for BCa treatment after intravesical instillation (Figure 3d; Zhang, Li,

et al., 2021). Why chose fluorinated chitosan (CS), the authors stressed that CS could cause significant necrosis and

deterioration in urothelial cells. In contrast, fluorinated cationic polymers could remarkably deliver drugs to tumors

with high permeability in the bladder wall, which could significantly enhance the therapeutic effect of intravesical

TABLE 2 Cu-based NMs for cancer monotherapy

Classification Cu-based NMs Parameters References

PTT Cu@CPP-t808-nm laser (1.6 W, 10 min) Weng et al. (2020)

O 808-nm laser (1 W cm

2

, 5 min) An et al. (2018)

Au@Cu

O 808-nm laser (1 W cm

2

, 5 min) Tao et al. (2019)

CuS 980-nm laser (2.48 W cm

2

, 3 min) Zheng et al. (2021)

CuS 808-nm laser (1 W cm

2

, 5 min) Qi et al. (2020)

CuS-Au 1064-nm laser (1 W cm

2

, 10 min) Wang, Yu, et al. (2020)

Gd/CuS 808-nm laser (0.5 W cm

2

, 10 min) Shi et al. (2019)

Gd/CuS@PEI-FA-PS 1064-nm laser (0.6 W cm

2

, 10 min) Zhang, Sun, et al. (2020)

CuS@MSN-TAT-RGD 980-nm laser (1.5 W cm

2

, 5 min) Li et al. (2018)

2x

S 635-nm laser (0.40 W cm

2

, 15 min) Zhao et al. (2020)

ZnPP/C

u2x

S 1064-nm laser (0.7 W cm

2

, 10 min) Yi et al. (2021)

CuS@GNPs 980-nm laser (0.8 W cm

2

, 10 min) Zhang, Xie, et al. (2021)

CuSe (2.0 W cm

2

, 10 min) 808-nm laser Wang, Miao, et al. (2017)

2x

Se (0.75 W cm

2

, 10 min) 1064-nm laser Zhang et al. (2016)

2x

Se@FCS 1064-nm laser (1.5 W cm

2

, 10 min) Zhang, Li, et al. (2021)

Fe-Cu@PANI 808-nm laser (1.5 W cm

2

, 5 min) Wang, Zhang, et al. (2021)

PDT Cu-Cy 360-nm laser (6 J cm

2

,20mWcm

2

, 5 min) Huang et al. (2019)

Cu-CDs LED (400–700 nm) light (40 mW cm

2

) Wang, Xu, et al. (2019)

Lip(ASC/PFH) 670-nm laser (0.48 W cm

2

, 10 min) Liu et al. (2018)

MOF-2 650-nm laser (50 mW cm

2

, 15 min) Zhang et al. (2018)

CuTz-1-O

@F127 808-nm laser (0.6 W cm

2

, 20 min) Cai et al. (2019)

PMOF White light (100 mW cm

2

, 5 min) Wang, Zhang, et al. (2021)

CIS 660-nm laser (1 W cm

2

, 10 min) Wang, Ma, et al. (2019)

SDT Cu-Cy 2 W US (2 W, 3 min) Wang et al. (2018)

RDT Cu-Cy X-ray (90 kVp, 30 mA, 5 Gy) Shrestha et al. (2019)

Cu-Cy X-ray (6 MV, 100 MU min

1

, 2 Gy) Chen et al. (2022)

CDT Cu-Cys 5 mg kg

1

Ma et al. (2019)

M-CeO

10 mg kg

1

Zhou, Li, et al. (2021)

CP 5 or 10 mg kg

1

Lin et al. (2019)

NCP 3 mg kg

1

Deng et al. (2022)

CPMP 10 or 20 mg kg

1

Yang, Tao, et al. (2021)

M-CSTD.NHAc/Cu(II) 0.8 μmol Song et al. (2021)

Cu-Mn bimetallic complex 4 μM, 8 μM, 16 μM Cao et al. (2019)

10 of 43 ZHONG ET AL.

instillation. Compared with the CS-modified Cu

2x

Se@CS (CC) NPs, the fluorescence signal of CF NPs in the bladder

was 5.3 times higher than that of the nonfluorinated counterparts of CC NPs, revealing the high transmucosal ability of

FCS. After further irradiation with a 1064-nm laser at 1.5 W cm

2

for 10 min, tumor growth was delayed, as visualized

by bioluminescence (BL) imaging. Collectively, these Cu-based NMs preliminarily demonstrated the feasibility of vis–

NIR light-excited PTT without significant systematic toxicity to animals.

Exogenous PTAs with high PCE, high absorbance in the NIR I/II regions, high accumulation in the target site, and

high safety determine their potential in cancer PTT. Copper-based NMs have exhibited good performance in the

abovementioned aspects for cancer PTT.

3.2 |Photodynamic therapy

In addition to the PTAs for PTT under light excitation, some photosensitizers (PSs) can also respond to UV–vis–NIR

light for PDT of cancer. As another light-triggered anticancer technique, PDT, which converts oxygen-containing sub-

stances into ROS to induce cancer cell apoptosis or necrosis, has been shown to have noninvasive features, high selec-

tivity, few side effects, and drug resistance (Veeranarayanan et al., 2018). According to the two different photochemical

reaction processes with or without the electron transfer process, PDT is usually divided into type I and type II PDT.

Type II PDT, which is mainly dependent on O

can generate

, while type I PDT can produce O



and OH (Zhao

et al., 2021). Therefore, different light-responsive PSs have been reported to produce ROS to induce cancer cell death

via apoptosis or other pathways. These PSs are usually incorporated with heavy atoms, which made them facing some

drawbacks of dark toxicity, short triplet-state lifetimes, and high cost. Instead, the design of heavy-atom free PSs has

FIGURE 3 Cu-based NMs for PTT. (a) Amorphous Ag

2x

S quantum dots for PTT of liver cancer. Reprinted with permission from

of Science. (d) Cu

2x

VCH GmbH

ZHONG ET AL.11 of 43

become popular owing to their superior photophysical and photochemical properties over the past few years (Van-

Nghia et al., 2021). For example, in type II PDT, copper-doped carbon dots (Cu-CDs) were prepared by the pyrolysis

method for PDT of both cervical cancer and neuroblastoma (Figure 4a; Wang, Xu, et al., 2019). Under light-emitting

diode (LED) light (400–700 nm) irradiation at 40 mW cm

2

, large amounts of

were generated by Cu-CDs. As rev-

ealed by both ABDA and RB, the

quantum yield of Cu-CDs were calculated to be 0.36, which was comparable to

most conventional PSs. In vitro HeLa cells and SH-SY5Y 3D multicellular spheroids (MCs) mimicking a tissue model

further exhibited an effective tumor suppression effect. As mentioned above, O

, as the source of

plays an essential

role in ROS production; unfortunately, the hypoxic condition in the TME severely reduces the quantum yield of

.To

relieve hypoxia, Au@SiO

@Cu

O (ASC) was loaded into O

self-enriched perfluorohexane (PFH), forming ASC/PFH

nanocomposites for enhanced PDT via a plasmonic resonance energy transfer (PIRET) process (Figure 4b; Liu

et al., 2018). In this work, plasmonic gold (Au) metal nanostructures were incorporated into Cu

O semiconductors. By

utilizing the PIRET process from Au to Cu

O, ASC showed a high

quantum yield of 0.71, with the help of a

FIGURE 4 Cu-based NMs for PDT. (a) Cu-CD for both human cervical cancer and neuroblastoma. Reprinted with permission from

with Cu

as the active center for

GmbH & Co. KGaA, Weinheim. (d) CuTz-1-O

@F127 for enhanced PDT of both cervical and breast cancer. Reprinted with permission from

Wiley-VCH GmbH

12 of 43 ZHONG ET AL.

sufficient O

supply delivered by PFH under 670-nm laser irradiation at only 0.48 W cm

2

. An in vivo study further

strongly demonstrated hypoxia relief and remarkable PDT therapeutic effects mediated by the ASC/PFH platform.

As the hallmarks of the TME, which contains hypoxia and high concentrations of GSH, reductive GSH within

tumor tissue is not beneficial for ROS accumulation in PDT. As a result, GSH should be considered to be depleted for

enhanced PDT. For this purpose, a nano-MOF of [CuL-(AlOH)

]n (MOF-2) was developed for GSH adsorption to

enhance the PDT of liver cancer (Figure 4c; Zhang et al., 2018). Therefore, the active Cu

could specifically bind –SH to

absorb GSH, thus directly decreasing the intracellular GSH concentration, followed by increasing the ROS level under

650 nm light irradiation due to the contribution of H

L of mesotetrakis(4-carboxylphenyl)porphyrin. Interestingly, this

MOF-2-mediated GSH-depleted PDT was comparable to the commercial antitumor drug camptothecin (CPT) in anti-

cancer treatment, making it a new PS candidate or anticancer drug in cancer therapy. However, it has been reported

that the binding ability of Cu

sites to sulfhydryl groups is much weaker than that of Cu

. Moreover, the authors did

not modulate the hypoxic TME. Not long after this work, smart CuTz-1-O

@F127 NPs were designed to synchronously

provide sufficient O

and deplete overexpressed GSH for more effective PDT against both cervical and breast cancer

(Figure 4d; Cai et al., 2019). First, in the presence of H

, the CuTz-1 MOF could function as an 808-nm laser-

activated PS to generate OH and O

, alleviating hypoxia for type I PDT. Second, they could also adsorb intracellular

GSH at the same time, which was favorable for PDT. Importantly, these NPs were biodegradable, which is of great

importance for the future transformation of nanomedicine in clinics.

Unlike the introduced PSs that were fabricated before biomedical application, the in situ synthesis of PSs with

mitochondria-targeting ability will achieve maximized phototoxic damage to tumor cells but minimized toxicity to nor-

mal cells. To realize this precise PDT, cancer-cell-activated AIE PSs (MOF-199) were reported, a Cu(II)-based MOF as

an inert carrier to deliver PS precursors. Via an in situ click reaction, PSs could be exclusively synthesized with cancer

cells for PDT of cervical cancer (Figure 4e; Wang, Zhang, et al., 2021). In detail, Cu

ions, trimesic acid, and two pho-

tochemically inert precursors of TPA-alkyne-2+and MePy-N

were used to form MOF-199 (PMOF) via de novo synthe-

sis. After F-127 coating, the PMOF NPs with a positive charge could target mitochondria. Then, due to the high

concentration of GSH in tumor cells, Cu

ions in PMOF could be reduced to Cu

ions, serving as a catalyst source for

the in situ click reaction between TPA-alkyne-2+and MePy-N

. In turn, the formed TPATrzPy-3+functioned as a PS

to produce

with bright red fluorescence emission properties. Owing to the existence of quaternary ammonium and

pyridinium units, TPATrzPy-3+was endowed with mitochondria-targeting features to amplify its ROS-mediated cell-

killing efficacy. This strategy provided new insight into the design of PDT systems.

Cu-based inorganic PSs have rarely been reported for PDT, especially those that can respond to NIR light for deep

cancer PDT. Much more effort should be devoted to developing Cu-based PSs for high-efficiency deep PDT of tumors

that are outside the scope of current UV–vis–NIR light irradiation.

3.3 |Sonodynamic therapy

PDT using light as the excitation source to activate PSs for ROS generation has been extensively studied. Even with NIR

light irradiation, the penetration depth of human tissues is still limited below 1 cm, which makes PDT suitable for the

treatment of superficial tumors (Liang et al., 2020; Yang, Wang, et al., 2021). In contrast to light, US, as a mechanical

wave, is characterized by a high penetration ability relying on different frequencies. To date, US with frequencies rang-

ing from kHz to MHz has been utilized as the trigger of sonosensitizers for SDT in the presence of O

or other sub-

strates. It was reported that the penetration depth in soft tissues could reach more than 10 cm, a distance that can meet

the needs of clinical theranostics, such as US imaging and high-intensity focused US (HIFU) therapy. In the process of

SDT, the US-induced cavitation effect and sonoluminescence effects have been widely acknowledged to explain the pos-

sible ROS generation mechanisms, although no definite conclusion has been put forwards (Ouyang et al., 2020).

PSs play a pivotal role in PDT, as do sonosensitizers. The efficacy of SDT is closely related to the properties of

sonosensitizers, which motivated the development of new types of acoustic wave-activated nanomaterials for enhanced

SDT (Lin et al., 2020). From the perspective of construction, sonosensitizers are mainly divided into three categories:

organic, inorganic, and organic/inorganic hybrid sonosensitizers that are mainly based on metallic oxide, noble metal,

carbon, silicon, and metal ions. For Cu-based sonosensitizers, copper-cysteamine (Cu-Cy) was first reported as a new

sensitizer to US for oxidative therapy of breast cancer (Figure 5; Wang et al., 2018). Under US (0.5 W cm

2

) irradiation

for 1 min, the fluorescence intensity of terephthalic acid (TA) gradually increased with increasing Cu-Cy doses, mean-

ing that sonochemical species formed by ultrasonic cavitation. In vitro and in vivo studies further confirmed the

ZHONG ET AL.13 of 43

apoptosis of tumor cells and delayed tumor growth of breast cancer under US irradiation (0.5 W cm

2

, 1.0 MHz). This

study expanded the application of Cu-Cy NPs in the field of SDT. After the discovery that Cu-Cy NPs could respond to

light, X-ray, and microwaves, US-excited Cu-Cy NPs for SDT were first reported in this work. Both ROS and cavitation

effects could be observed in this process. However, whether other types of Cu-based NMs can function as

sonosensitizers should be studied to expand their application in the field of SDT.

3.4 |Radio-dynamic therapy

In addition to US, which has high penetration ability in theranostics, X-ray has also been used for CT imaging and

radiotherapy (RT) in clinical practice and can easily penetrate as deeply as necessary into patients (Zhong et al., 2019).

Applying X-ray as the stimulus of PSs, ROS can also be produced for cancer therapy, forming a new type of X-ray

induced photodynamic therapy (X-PDT), equal to RDT launched in 2006 (Chen & Zhang, 2006). However, most of the

GmbH & Co. KGaA, Weinheim

14 of 43 ZHONG ET AL.

widely used PSs cannot be stimulated by X-ray due to the wide mismatch of the energy gap between them. To convert

high-energy X-ray (keV–MeV) into UV–vis luminescence (eV), many types of energy transducers have been developed

for RDT, including scintillating NPs (ScNPs), persistent luminescence NPs (PLNPs), aggregation-induced emission

(AIE)-based NPs, nanoscale MOFs (nMOFs), and others (Zhong et al., 2021). However, the majority of the

abovementioned RDT systems, which combine energy transducers and PSs, suffer from the limited loading capacity of

PSs and fluorescence resonance energy transfer (FRET) efficiency, thus leading to nonideal outcomes.

Unlike the FRET-based strategy, we found that the NaCeF

:Gd,Tb nanoscintillator itself could function as an X-ray

responsive PS for RDT, with no need to conjugate organic PSs (Zhong et al., 2019). Similarly, among these sensitizers

that can directly respond to X-ray, Cu-Cy nanoparticles not only responded to US mentioned above but also were

responsive to X-ray to generate

for RDT of colorectal cancer (Figure 6a; Shrestha et al., 2019). Based on their previ-

ous pilot study that measured the survival of a large cohort of mice after receiving X-ray activation of Cu-Cy NPs, they

further conjugated a pH-low insertion peptide (pHLIP) onto Cu-Cy NPs to facilitate active targeting of CuCy-pHLIP to

low-pH tumors. Under UV light irradiation at 365 nm, an alternative to X-ray irradiation, Cu-Cy NPs emitted red fluo-

rescence at 607 nm with a shoulder at 633 nm, accompanied by

generation. The mechanism of X-ray-stimulated

FIGURE 6 Cu-based NMs for RDT. (a–c) CuCy-pHLIP conjugates for RDT of colorectal cancer. Reprinted with permission from

ZHONG ET AL.15 of 43

Cu-Cy NPs for

generation was similar to the process of light-activated PDT (Figure 6b). In vivo studies demon-

strated that by pHLIP conjugation, Cu-Cy nanoparticles effectively delayed tumor growth in both male and female mice

(Figure 6c). This might be the reason why pHLIP could enhance the binding of Cu-Cy to tumor cells since

is very

short-lived at 4μs. Therefore, CuCy-pHLIP has been successfully attempted as an X-ray-responsive sensitizer

for RDT.

Excited by the satisfying results of Cu-Cy-based RDT in the laboratory, for the first time, they further used a

linear accelerator and built deep-seated tumor models to mimic the clinical conditions, aiming to judge the

effectiveness and its effects on cell migration and proliferation (Figure 6d; Chen et al., 2022). They found that

Cu-Cy-mediated RDT could inhibit the proliferation and migration of HepG2, SK-HEP-1, Li-7, and 4T1 cells in a

dose-dependent manner. MRI assessment visualized that the growth of deeply located tumors in mice and rabbits

was inhibited by X-ray-irradiated Cu-Cy. In addition, Cu-Cy-mediated RDT inhibited tumor cell proliferation and

migration by upregulating proliferating cell nuclear antigen (PCNA) and E-cadherin. The possible influences of

RDT might also include oxidative stress, killing, and immunity enhancement, which might be beneficial to cancer

treatment. Overall, these systematic studies declared that Cu-Cy NP-mediated RDT has promising prospects in

clinical applications. Unfortunately, there is a lack of research on Cu-based PSs that can respond to X-ray for RDT,

such as Cu-based sonosensitizers.

3.5 |Chemodynamic therapy

According to the position of excitation sources relative to the tumor tissues, ROS can be produced by not only external

stimuli, including light, US, and X-ray but also chemical energy (Zhong et al., 2021). CDT has been recognized as a

tumor-specific treatment with high dependence on the TME. It uses Fenton/Fenton-like agents to convert H

into

cytotoxic OH, inducing tumor cells to undergo apoptosis and necrosis (Tang et al., 2019). Generally, Fenton/Fenton-

like agents are mainly based on transition metal ions of Fe, Co, Ni, Cu, Mn, and heavy metal ions such as Pt and

Ce. For instance, Cu-Cy NPs with multiple faces were used as light-, US-, and X-ray-responsive sensitizers for ROS gen-

eration. In this study, self-assembled Cu-Cys NPs were utilized for GSH-activated CDT of drug-resistant breast cancer

(Ma et al., 2019). In brief, after endocytosis, the Cu

ions in Cu-Cys NPs were first reduced by intracellular GSH to

form Fenton-like agents of Cu

ions, followed by interaction with in situ H

to produce OH in the weakly acidic

TME. Compared with DOX administration, drug-resistant breast cancer showed delayed tumor growth, meaning that

they were much more sensitive to Cu-Cys-based CDT.

However, although this work cleverly exploited the high concentration of GSH in the TME to reinforce CDT, the

CDT performance is still limited by certain other issues, including the low content of endogenous H

and the rela-

tively higher pH of solid tumors (6.5–6.8), which do not meet the strict reaction conditions for most Fenton/Fenton-like

reactions. To supply additional H

into the tumor cells and reduce the dependence of Fenton/Fenton-like agents on

low pH, a series of metal-doped cerium peroxides (M-CeO

) with high pH activation and H

self-supply were fabri-

cated for the ultrasensitive CDT of breast cancer (Figure 7a; Zhou, Li, et al., 2021). These doped metal ions included

,Cu

,Mn

,Co

,Ce

,Cr

,Al

, and Ru

. Compared with undoped CeO

, these metal ions endowed it with

high catalytic efficacy at a high pH of 7.0 (40- to 60-fold increase). In addition, as metal peroxides, CeO

functioned as

the donor of H

to relieve the insufficient endogenous H

level for enhanced CDT. Therefore, this strategy signifi-

cantly improved tumor cell sensitivity to CDT.

With the same strategy of self-supplying H

, copper peroxide (CP) nanodots were reported much earlier than

CeO

by Prof. Chen and coworkers (Lin et al., 2019). After endocytosis, the dissociation of CP nanodots could be

accelerated due to the acidic environment of endo/lysosomes, allowing for the subsequent enhanced CDT. The gen-

erated OH caused tumor cell death via the lysosome-associated pathway via lipid peroxidation (LPO)-mediated

lysosomal membrane permeabilization. As a result, lysosomes have emerged as specific targets for cancer treat-

ment. Despite the appropriate pH (4.5–5.0) of lysosomes for the Fenton reaction, the catalytic agents will rapidly

escape to the cytoplasm, thus limiting the action time of CDT. Therefore, it is highly meaningful to anchor the cata-

lytic agents inside the acidic lysosome, aiming for a lengthening time to decompose enough catalytic ions for CDT.

More recently, they further prepared a series of nano copper peroxides (NCPs) with tunable acid dissociation con-

stant (pKa) values from 5.2 to 6.2 for H

self-supplying CDT (Figure 7b; Deng et al., 2022). Intracellular traffick-

ing studies revealed that NCP with a lower pKa value (pKa 5.2) retained a longer time in lysosomes, followed by

decomposition of enough Cu

ions and H

for a robust Fenton reaction. Most importantly, the Fenton reaction

16 of 43 ZHONG ET AL.

was strictly processed within the lysosomal compartment, avoiding interference from cytoplasmic GSH. Overall,

this work provides a more precise strategy for enhanced CDT.

Recently, nanozyme-based CDT has become an attractive cancer treatment because of its low side effects and high

efficacy. The construction of a single catalyst with multiple enzyme properties for enhanced CDT is still a major chal-

lenge. For this purpose, seven types of bimetallic nanoparticles were synthesized with MOF (MIL-101) as a stable host

for active metal ion delivery for enhanced CDT of breast cancer (Figure 7c; Yang, Tao, et al., 2021). These seven alloyed

NPs were 6.0 wt%Cu-Pd@MIL-101, 7.5 wt%Cu-Pd@MIL-101, 9.0 wt%Cu-Pd@MIL-101, 9.5 wt%Cu-Pd@MIL-101, 10.1

wt%Cu-Pt@MIL-101, 9.1 wt%Co-Pt@MIL-101, and 8.7 wt%Ni-Ru@MIL-101. Among them, Cu-Pd@MIL-101 with an

alloy loading of 9.5 wt% (9.5% CPMP) was found to have the highest peroxidase (POD) and superoxide dismutase (SOD)

mimic activities and GSH depletion ability. This work was considered another credible strategy for the design of

enhanced CDT.

The blood–brain barrier (BBB) is a major challenge for the chemotherapy of orthotopic glioma. Similarly,

these chemodynamic agents also hardly cross the BBB to reach tumor tissues. Herein, based on the recognition

between β-cyclodextrin (CD) and adamantane (Ad), supramolecular assembled tectodendrimers with acetyl termini

(M-CSTD. NHAc) were prepared for glioma theranostics (Figure 7d; Song et al., 2021). In this core–shell structure,

thecoreofCSTDswascomposedofCD-modifiedgeneration 5 (G5) poly(amidoamine) (PAMAM) dendrimers and

Ad-functionalized G3 PAMAM dendrimers (G3. NH

-Ad) were the shell. Following modification with pyridine,

FIGURE 7 Cu-based NMs for CDT. (a) M-CeO

for pH-activated and H

self-supply-mediated CDT of breast cancer. Reprinted with

for specific CDT

supplementation and

GmbH. (d) M-CSTD. NHAc/Cu(II) complexes self-supply H

for enhanced CDT of orthotopic glioma. Reprinted with permission from

ZHONG ET AL.17 of 43

ions could be complexed onto the shell, dermorphin could be loaded for BBB crossing, and arginine-

glycine-aspartic acid (RGD) peptide could be further anchored for active targeting to form the final M-CSTD.

NHAc/Cu(II) complexes. After intravenous injection, this intelligent platform could cross the BBB and target

orthotopic glioma for CDT, causing LPO, cell cycle arrest, and cell apoptosis. In vivo CDT efficacy was further

confirmed through the elevated survival rate and relieved histological examinations. Collectively, these Cu-based

chemodynamic agents enhanced the precision and effect of CDT by modulating the hallmarks of the TME,

including pH, H

, and GSH, to relieve harsh conditions or utilize these features to initiate CDT with minimized

side effects on normal cells.

4|Cu-BASED NMs FOR COMBINED CANCER THERAPY

In most cases, the antitumor outcomes of combined therapies are not an additive effect simply by summing the effect of

each therapy alone but rather a synergistic effect (Liu et al., 2019). Cu-based NMs with unique properties have achieved

success in cancer monotherapy, including PTT and dynamic therapies of PDT, SDT, RDT, and CDT. However, the mul-

tiple physical, chemical, and catalytic properties of Cu ions enable Cu-based NMs to wear many hats, which will realize

satisfactory therapeutic effects of cancer combination therapy (Table 3).

4.1 |PTT-based combined cancer therapy

Although some achievements have been made in the field of tumor optical therapy, certain disadvantages or biological

barriers still exist that limit the effectiveness of PTT. For example, the greatest drawback is the limited depth of light

penetration due to the decreased laser intensity, the overexpression of heat shock protein (HSP) that makes cancer cells

resistant to hyperthermia, and even overheating or inhomogeneous heat distribution within healthy tissue or tumors.

However, combining PTT with other treatment modalities would achieve unexpectedly good results because hyperther-

mia can increase regional blood flow, speed up cellular metabolism, and enhance membrane permeability, which is

also beneficial for the cellular uptake of drugs and many types of sensitizers, thus providing favorable conditions for

chemotherapy and many dynamic therapies (Poudel et al., 2019). This is the theoretical basis of combination therapy of

PTT with other therapies. Considerable attention has been devoted to combining PTT with many other treatment

modalities (Xie et al., 2020). Below, we introduce PTT-based combination therapy with chemotherapy, PDT, RT, CDT,

SDT, gene therapy, and immunotherapy.

4.1.1 | Combination of PTT with chemotherapy

For most cancers, chemotherapy is still considered a prominent strategy in the clinic. However, the aimless distribution

of chemodrugs in the body, in other words, the nonspecific target to the tumor site, will cause underdose but induce

systemic toxicity and side effects on healthy cells (Yan et al., 2020). To deliver targeted chemotherapeutic drugs to the

tumor site, drug delivery systems (DDSs) based on organic, inorganic, or hybrid DDSs as trucks would enhance the

drug contents within tumors (Yan et al., 2021). To function as high-efficiency DDSs, the “five features principle”should

be satisfied, including “long circulation”,“enhanced tumor accumulation”,“deep tumor penetration”,“efficient cellular

internalization”, and “drug release”(Yong et al., 2020).

Cu-based NMs can act not only as PTAs but also as DDSs to combine PTT and chemotherapy to achieve synergetic

anticancer effects. For example, copper-doped layered double hydroxide (Cu-LDH) NPs were chosen as PTA and the

DDS of two FDA-approved chemodrugs, that is, 5-Fluorouracil (5-FU) and albumin-bound paclitaxel (nAb-PTX) for

PTT and chemotherapy of breast cancer (Liu, Liu, Zhang, et al., 2021). The two drugs were functionally complemen-

tary; 5-FU inhibited thymidylate synthase (TS) activity to prevent DNA/RNA synthesis, while PTX inhibited microtu-

bule disassembly to disrupt normal dynamic reorganization of the microtubule network to induce cell apoptosis. 5-FU/

Cu-LDH@nAb-PTX showed pH-sensitive release, and heat facilitated the on-demand release of 5-FU and nAb-PTX.

Under 808-nm laser irradiation at 0.75 W cm

2

for 3 min, a very low dose of 5-FU (0.25 mg kg

1

) and nAb-PTX

(0.50 mg kg

1

), which were 8–50 times less than those used in other nanodrugs, could effectively eliminate 4T1 tumors

in vivo with no observable side effects.

18 of 43 ZHONG ET AL.

TABLE 3 Cu-based NMs for cancer combination therapy

Classification Cu-based NMs Parameters References

PTT–chemotherapy 5-FU/Cu-LDH@nAb-

PTX

808-nm laser (0.75 W cm

2

, 3 min)

5-FU (0.25 mg kg

1

), nAb-PTX

(0.50 mg kg

1

)

Liu, Liu, Zhang,

et al. (2021)

PDC/P@HCuS 1060-nm laser (2.7 W cm

2

, 6 min)

P@HCuS (25 mg kg-

), PDC (4 mg kg

1

)

Sun et al. (2019)

BSD 808-nm laser (1.0 W cm

2

, 5 min)

Cu (5 mg kg

1

)

Pan et al. (2021)

DSF@PVP/Cu-HMPB 808-nm laser (1.5 W cm

2

)

DSF@PVP/Cu-HMPB (20 mg kg

1

)

Wu et al. (2020)

P-V@TPDOX 808-nm laser (1 W cm

2

)

200 μgml

1

, 200 μl

Ji et al. (2021)

AuNRs-CTN@THA 808-nm laser (1 W cm

2

, 3 min)

CTN (2 mg kg

1

day

1

6 days)

Gao et al. (2020)

PTT–PDT TPP-ZC-IR-PNPs 808-nm laser (1 W cm

2

, 5 min)

ZCNP (5 mg kg

1

), IR 780 (2.5 mg kg

1

)

Ruttala et al. (2021)

B-CuS-FA 808-nm laser (1.0 W cm

2

, 8 min)

200 μgml

1

Jana et al. (2020)

MCNs-Cu 808-nm laser (1 W cm

2

)

10 mg kg

1

You et al. (2020)

Cu-DhaTph 808-nm laser (1.5 W cm

2

, 10 min)

2mgml

1

, 100 μl

Feng et al. (2021)

MCIH 808-nm laser (0.76 W cm

2

, 10 min)

2mgml

1

, 100 μl

Sun et al. (2020)

PhA@NanoICG 808-nm laser (1.0 W cm

2

, 5 min)

630-nm laser (0.5 W cm

2

, 3 min)

ICG (1.0 mg kg

1

), PhA (0.8 mg kg

1

)

Chen, Zuo, et al. (2021)

PTT–RT CuS/

131

I-PEGDA 915-nm laser (1.0 W cm

2

,43C for

20 min) 1

915-nm laser (1.0 W cm

2

,43C for

10 min) 2

CuS NPs (9.5 mg kg

1

131

I (50 μCi)

Meng et al. (2018)

AuPt@CuS 808-nm laser (1.0 W cm

2

, 10 min)

2.0 mg ml

1

,25μl

X-ray (50 kV, 75 μA, 10 min)

Cai et al. (2021)

PTT–CDT BSA-CuFeS

808-nm laser (1.5 W cm

2

, 5 min)

15 mg kg

1

Chen, Luo, et al. (2019)

CuFe

808-nm laser (1.0 W cm

2

, 5 min)

10 mg kg

1

Liu, Liu, Wan,

et al. (2021)

808-nm laser (0.5 W cm

2

, 5 min)

20 mg kg

1

Wang, An, et al. (2020)

PEG-Cu

Se 1064-nm laser (0.75 or 1.0 W cm

2

, 10 min)

5mgkg

1

Wang, Zhong,

et al. (2019)

TRF-mCuGd 808-nm laser (0.8 W cm

2

, 10 min)

2mgkg

1

Zhang, Xie, et al. (2021)

BP@Cu

0.4

@PEG-RGD 808-nm laser (1.0 W cm

2

, 2 min)

100 ppm

Lyu et al. (2020)

PTT–SDT PCPT 808-nm laser (1.0 W cm

2

, 7 min)

US (1.0 MHz, 1.0 W cm

2

, 60% duty cycle,

5 min)

20 mg kg

1

Liang et al. (2019)

(Continues)

ZHONG ET AL.19 of 43

In addition to copper-doped LDH, hollow copper sulfide (HCuS) NPs were also proven suitable for drug loading.

However, during circulation before reaching the tumor site, the premature drug is very likely to happen from the naked

HCuS. Therefore, developing a stimuli-responsive gatekeeper on the surface of the pores is a good choice. Moreover,

molecular targeted prodrugs might be more effective in ameliorating chemotherapy. Herein, amphiphilic fluorescence-

labeled copolymer (fPEDC)-coated HCuS NPs were used to load molecular-targeted prodrugs (PDCs), forming

PDC/P@HCuS for chemo-PTT of breast cancer (Sun et al., 2019). In the small-molecule PDC of cRGD-SMCC-DM1,

maytansinoid (DM1) worked as a cytotoxic agent for chemotherapy; cRGD was a homing peptide; and uncleavable

thioether (SMCC) functioned as the linker. Compared with free DM1, peptide-conjugated DM1 (PDCs) could target

integrin α

by cRGD, which was cytotoxic to MDA-MB-231 cells, as they were confirmed to be α

-positive. In the

drug release experiment, DM1 was stable in PDC when dispersed at pH 7.4. At pH 5.2, the cumulative drug released

from PDC/P@HCuS was improved from 34.4% to 61.3% compared with fPEDC noncoated PDC/HCuS, revealing the

pH-responsive feature of fPEDC for controlled drug release. From another point, the weakly alkaline pyridine with

PDC had a relatively low level of protonation in the high-redox TME, which played a more key role in drug release than

pH. Under 1060-nm laser irradiation, this process could be further facilitated for burst release. In vitro studies demon-

strated that this strategy with high cytotoxicity to tumor cells was mainly based on affecting the cell cycle, cytoskeleton,

cellular proteomics, and permeability. In vivo study further indicated that only the combination therapy could actualize

the best efficacy.

Despite the intelligent and responsive properties of the PDC/P@HCuS nanoplatform, the fabrication process was

complex and time consuming. The strategy of in situ drug generation and controllable loading looks more attractive.

TABLE 3 (Continued)

Classification Cu-based NMs Parameters References

PTT–gene therapy RGD-CuS DENPs/

pDNA

1064-nm laser (0.6 W cm

2

, 5 min)

[Cu] =(4 mM, 100 μl), pDNA (10 μg)

Ouyang et al. (2021)

PTT–immunotherapy CuS NPs-PEG-Ma 808-nm laser (0.45 W cm

2

, 5 min)

CuS NPs-PEG-Mal (15 mM, 50 μl)

anti-PD-L1 (50 μg)

Wang, He, et al. (2019)

AM@DLMSN@CuS/

R848

980-nm laser (1.0 W cm

2

, 10 min)

CuS (30 mg kg

1

), R848 (3 mg kg

1

)

AUNP-12 (5 mg kg

1

)

Cheng et al. (2020)

CSP@IL-12 1064-nm laser (0.6 W cm

2

, 5 min)

CSP (172.4 μg), IL-12 (10 μg)

Lin et al. (2021)

Chemotherapy–CDT Cu-TG 9.2 mg ml

1

,50μl Yuan et al. (2020)

Chemotherapy–ST–CDT PGC-DOX PGC (10 mg kg

1

), DOX (5.7 mg kg

1

) Fu et al. (2021)

Chemo-gas therapy–CDT AIBA@FeCuS-FeCO US (1 W cm

2

, 50% duty, 3 min)

US (1 W cm

2

, 100% duty, 5 min)

AIBA@FeCuS-FeCO (500 μgml

1

, 150 μl)

DSF (2 mg kg

1

)

Sun, An, et al. (2021)

PTT–PDT–chemo-

immunotherapy

FA-CD@PP-CpG 808-nm laser (0.987 W cm

2

, 5 min)

650-nm laser (4.5 mW cm

2

, 5 min)

Chen, Zhou, et al. (2019)

SDT–CDT PtCu

US (3.0 W cm

2

, 35 kHz, 10 min)

10 mg kg

1

Zhong et al. (2020)

MWDTT–chemotherapy RBC-Zr@APC/C MW (0.9 W, 5 min), 50 mg kg

1

Chen, Wu, et al. (2021)

therapy–PTT–PDT–CDT UCCZ-FA 980-nm laser (1 W cm

2

, 5 min)

1mgml

1

, 200 μl

Wang, Ji, et al. (2020)

PDT–CDT–ICB Cu-TBP-αPD-L1 LED lamp (650 nm, 100 mW cm

2

, 30 min)

TBP (0.2 μmol)

αPD-L1 (75 μg3)

Ni et al. (2019)

PTT–PDT–CDT–CIT–

immunotherapy

O@CaCO

-anti-

CD47

1064-nm laser (0.5 W cm

2

, 5 min)

O@CaCO

(5 mg kg

1

), anti-CD47

(100 μg)

Chang et al. (2020)

20 of 43 ZHONG ET AL.

For example, CuS and copper diethyldithiocarbamate (Cu(DTC)

) were coloaded with bovine serum albumin (BSA) via

a one-pot biomineralization-mimicking synthesis, forming BSD NPs, which were prepared for chemo-photothermal

therapy of melanoma (Figure 8a; Pan et al., 2021). By providing Cu

2

, and DTC in water, the PTA of CuS and

chemodrug Cu(DTC)

could be concurrently synthesized in situ with BSA as the biomacromolecular template. Of these,

Cu(DTC)

was originally the main metabolite of the alcohol-abuse drug disulfiram (DSF), but it was highly cytotoxic to

cancer cells and has been identified as an anticancer drug. Overall, NIR light-irradiated BSD NPs efficiently arrived at

tumor sites and ablated B16 tumors. Similarly, DSF was also used as the prodrug in another study, but the difference

was that DSF and Cu

were separated before reaching the tumor. Only under the stimulus of endogenous mild acidity

within tumors could make cytotoxic bis(N,N-diethyl dithiocarbamato)copper(II) complexes (CuL

) be formed via a

DSF-Cu

chelating reaction. This was due to the pH-responsive biodegradation of hollow mesoporous Prussian blue

(HMPB) nanocages (Figure 8b; Wu et al., 2020).

For cancer chemotherapy, multidrug resistance (MDR) usually occurs with poor treatment outcomes. Overcoming

MDR is still a challenge in developing effective DDSs. Herein, a Cu

2x

Se-based photothermal vector (PT-V) was synthe-

sized to effectively deliver triphenylphosphine (TP)-modified DOX (TPDOX), forming PT-V@TPDOX to mitochondria

to overcome MDR cancer (Figure 8c; Ji et al., 2021). This formulation with high toxicity toward MCF-7/ADR cells was

produced via four pathways: (1) folic acid (FA)-receptor mediated endocytosis, (2) photothermally controlled drug

release, (3) TP-directed mitochondrial targeting of TPDOX, and (4) inhibition of P-glycoprotein (P-gp)-mediated drug

FIGURE 8 Cu-based NMs for combined PTT with chemotherapy. (a) In situ drug generation of cu(DTC)

for chemo-photothermal

GmbH & Co. KGaA, Weinheim. (c) PT-V@TPDOX for combined PTT-chemotherapy of multidrug-resistant human breast cancer. Reprinted

Society of Chemistry

ZHONG ET AL.21 of 43

efflux for enhanced drug retention. Finally, PT-V@TPDOX showed a powerful inhibition rate of 97.3% against MDR

tumors.

On-demand and stimuli-responsive drug release plays important roles in elevating the efficacy of chemotherapy and

reducing side effects. However, according to the “five features principle”of deep tumor penetration, DDSs with the abil-

ity to carry chemo-drugs into hypoxic areas that lack or are far from blood vessels are an important parameter to assess

their efficacy in chemotherapy. To validate this possibility, a hybrid nanocomposite (AuNRs-CTN@THA) was designed

for synergetic chemo-PTT of deep tumors (Figure 8d; Gao et al., 2020). Thiolated hyaluronic acid (THA) is a ligand rec-

ognizer that targets CD44 receptors that are highly expressed on B16F10 cells. CTN, a chemotherapeutic agent of [Cu

(ttpy)(NO

)

] (ttpy =40-p-tolyl-2,20:6,200-terpyridine) (CTN), has high DNA affinity to possibly induce DNA cleavage

activity. Gold nanorods (AuNRs), of course, are famous effective PTAs. All of these factors contributed to photo-

thermally enhanced drug penetration and retention, which was validated by using a 3D tumor spheroid model and mel-

anoma tumor-bearing mice, respectively. This study was a striking example to stress the significance of deep tumor

penetration in chemotherapy. With improved delivery, even distribution, reduced systemic toxicity, and precisely con-

trolled drug release of chemotherapeutics by light, tumor cells appeared more vulnerable to chemotherapy, suggesting

the greater benefits of combined PTT-chemotherapy.

4.1.2 | Combination of PTT with PDT

PTT and PDT are the two types of burgeoning therapeutic modalities triggered by light in cancer therapy. Because of

their similar responsiveness to light, PSs and PTAs, joint PTT with PDT has been considered a feasible way to improve

synergistic anticancer effects (Chu et al., 2022; Gai et al., 2018). One reason is that PTT can increase O

perfusion and

nanoagent penetration by hyperthermia effects; another is that some nanoagents possess both PTT and PDT effects

under irradiation with one or two light sources, which simplifies the operation process.

Specific chemical reaction-based bioorthogonal chemistry has emerged as a powerful tool in cancer therapy

(Liu, Hu, Wu, et al., 2021). Due to the highly catalytic Cu(I) and the highly specific bioorthogonality of azides and

alkynes, Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition (CuAAC) reactions have drawn worldwide attention in various

fields, including cancer therapy. Recently, heterogeneous Cu nanoparticles (CuNPs) formulated in situ on mesoporous

carbon nanospheres (MCNs) have been utilized for bioorthogonally assisted PTT and PDT combination therapy of

cervical cancer via an NIR light-promoted CuAAC reaction (Figure 9a; You et al., 2020). In the MCNs-Cu system,

MCNs could act as PSs for PDT, followed by oxidizing Cu(0) to Cu(I) by ROS to enhance the CuAAC reaction. Simulta-

neously, MCNs could also function as PTAs to transform NIR light into heat, which could further accelerate the

catalytic process by increasing the local temperature. As expected, the MCNs-Cu nanocatalyst significantly inhibited

tumor growth and protected healthy tissues. Therefore, this work provides a greater possibility to realize bioorthogonal

chemistry-mediated cancer therapy. In addition to MCNs, another phototherapeutic agent with both sufficient PCE and

highly efficient ROS production was also reported in another study, since this was still a huge challenge. In this study,

carrier-free PhA@NanoICG was synthetized via copper coordination-driven self-assembly for PTT-PDT of breast cancer

(Figure 9b; Chen, Zuo, et al., 2021). Indocyanine green (ICG), as the PTA and PS of pheophorbide A (PhA), was tightly

connected with Cu

and acted as a bridge. Notably, via J-aggregation, the absorption peak of NanoICG was redshifted,

which significantly increased the PCE of ICG for PTT under 808-nm laser irradiation. Once accumulated in tumors,

PhA@NanoICG could be disassembled due to the weak acidity and highly reductive GSH. Since then, the tumors that

lost antioxidant-defense ability would improve the sensitivity to ROS that were generated from PhA under 630-nm laser

irradiation. In summary, a carrier-free nanoagent with dual acidity/GSH responsiveness was successfully developed for

tumor phototherapy.

To achieve synergistic PTT-PDT, three challenges remain: complex conjugation chemistry, absorption wavelength

mismatch, and inadequate biodegradability of the nanoagents. The above two examples solved the first issue with click

chemistry or coordination chemistry, while the remaining two issues should be addressed. Herein, CuS nanodot-

anchored FA-modified black phosphorus nanosheets (BP-CuS-FA) were designed (Figure 9c; Jana et al., 2020). CuS

nanodots with high absorbance in the NIR region contributed to the good performance in PTT. In addition, BP func-

tioned as a PS to generate

for PDT, as revealed by both the DPBF and ABDA probes. Under the guidance of FA,

folate receptor-overexpressing 4T1 tumors were significantly damaged after synergistic PTT–PDT treatment. More

importantly, both XPS and NMR spectrum analyses proved that BP nanosheets were dissociated into PO

43

anions

under laser irradiation, enabling the degraded species to be excreted efficiently from the kidney.

22 of 43 ZHONG ET AL.

FIGURE 9 Cu-based NMs for combined PTT with PDT. (a) Heterogeneous MCN-Cu nanocatalyst for PTT-PDT of cervical cancer via

Elsevier Inc. (c) Clearable BP-CuS-FA nanoconjugate for synergistic PTT-PDT of breast cancer. Reprinted with permission from Jana

S-activable PTT-PDT of human colon cancer by Cu(II)-porphyrin-derived

ZHONG ET AL.23 of 43

In fact, the BP-CuS-FA-based PTT-PDT strategy relied on two separate PTA and PS, and constructing a simple struc-

ture with both faces of PTA and PS through a step-economical approach method is highly imperative and challenging.

To meet this challenge, Cu(II)-porphyrin-derived nanoscale covalent organic frameworks (COFs) of Cu-DhaTph were

fabricated to realize PTT/PDT via an in situ sulfidation reaction by utilizing the high content of H

S in colon tumor

sites (Figure 9d; Feng et al., 2021). The concentration of H

S in colon tumors ranges from 0.3 to 3.4 mM; specifically,

with high affinity to S

2

could grab H

S to form photothermal CuS for PTT. After CuS formation, the released

DhaTph responded to the same light to generate

for PDT consequently. In this way, endogenous H

S-triggered in

situ PDT/PTT was realized for local colon cancer. Under one or two light irradiation cycles, two different physical and

chemical processes could be synchronously initiated, generating heat and oxidase stress to kill cancer cells in a

collaborative way.

4.1.3 | Combining PTT with radiotherapy

RT, which consists of external beam radiotherapy (EBRT) and internal radioisotope therapy (RIT), or brachytherapy,

has been widely used as the mainstream treatment for more than 50% of patients with cancer for curative or palliative

purposes (De Ruysscher et al., 2019). Regardless of the subtype of RT applied, O

is essential to fix radioactive ray-

generated ROS to further improve the RT effect. Unfortunately, tumor hypoxia hinders the desired anticancer effect of

RT. It has been reported that PTT with mild heat can increase blood supply by elevating the blood flow rate and vasodi-

lation (Lyu et al., 2020). In turn, NIR light-excited PTT still suffers from limited tissue penetration depth, especially in

inner tumors. Therefore, rational integration of PTT with RT is highly promising for improving antitumor efficacy.

Nanotechnology provides opportunities to bridge RT and photothermal ablation of tumors. For brachytherapy, clini-

cally radioactive sources such as

125

I beads were found to offer inhomogeneous dose distribution or regression by local

implantation. This would result in a steep dose gradient and poor treatment. To improve the homogeneity and retention

of the radiotherapeutic agent

131

I, an NIR-triggered in situ hybrid hydrogel was designed for PTT-enhanced RT of breast

cancer (Figure 10a; Meng et al., 2018). In this system,

131

I-labeled CuS NPs (CuS/

131

I) were the main part that func-

tioned as

131

I-based brachytherapy and CuS-based PTT; poly(ethylene glycol) double acrylates (PEGDA) as a polymeric

matrix served as the host; and the thermal initiator 2,20-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH)

was used to initiate the polymerization of PEGDA upon 980-nm laser irradiation. After in situ gelation, CuS/

131

I NPs

were locally fixed inside the tumor for a long time without obvious leakage into normal organs. Further assisted by

PTT-induced hypoxia relief, a synergistic PTT–RT effect was realized by CuS/

131

I-PEGDA/AIPH, which was far better

than that of CuS/

131

I NPs.

In addition to hydrogel-mediated brachytherapy, high-atomic number elemental nanostructure-based NPs have

increasingly positive effects on the sensitivity of cancer cells to EBRT. Combining the photothermal agent of CuS NPs

with noble metal NPs, a heterostructure can be established to enhance the optical absorption cross sections and then

improve the photothermal performance of CuS NPs. Meanwhile, intraparticle charge transfer can be boosted to speed

up chemical cascade reactions induced by radiation for more energy deposition in cancer cells. Based on this principle,

a strong plasmon–plasmon coupling T80-AuPt@CuS heterostructure was constructed for radio-photothermal therapy

of breast cancer (Figure 10b; Cai et al., 2021). In this heterostructure, the surface plasmon resonance (SPR) of AuPt NPs

led to a localized electromagnetic field at their interface upon NIR light irradiation, which increased the mass extinc-

tion coefficient of AuPt@CuS to be 4.50 L g

1

, much higher than 2.70 L g

1

of the CuS NPs. In the study of

radiation-induced chemical cascade reactions for ROS amplification, three different cytotoxic ROS, incluidng OH,

O



, and

were produced under X-ray irradiation. From the perspective of band-edge positions, this was because

both e



and e



were able to directly transfer to O

and H

, generating O



and OH, respectively. In addition,

depleted highly reductive GSH for ROS accumulation. By taking terephthalic acid (THA), 3-bis(2-methoxy-4-nitro-

5-sulfopheh-yl)-2H-tetrazolium-5-carboxanilide (XTT), and singlet oxygen sensor green (SOSG) as indicators, OH,

O



, and

were indeed produced with high efficiency, respectively. Due to its high performance in photothermal

and photocatalytic processing, synergistic photothermal ablation, and radiotherapy were achieved without incurring

significant side effects.

The above two works successfully utilized CuS NPs plus with β-ray-emitting nuclides or radiosensitizers of heavy

metallic AuPt for synergistic radio-photothermal therapy for breast cancer therapy. PTT has been reported to perform

multiple functions, including preventing DNA damage repair, arresting the cell cycle, dilating blood vessels, and

24 of 43 ZHONG ET AL.

relieving hypoxia. All these changes contribute to the high susceptibility of tumor cells to RT, consequently causing less

damage to the surrounding normal tissues (Xu & Pu, 2021).

4.1.4 | Combination of PTT with CDT

CDT has been proven to have high specificity and selectivity between cancer cells and normal cells (Yang, Gong,

et al., 2021). However, monotherapy alone is still not strong enough to fight against cancer. Accompanied by other

approaches, such as speeding up the reaction rate, supplying additional H

, and modulating GSH and pH would

improve the performance of CDT (Wang, Zhong, et al., 2020). To date, most of the designed Fenton/Fenton-like agents

can generate OH only in a narrow pH range of 3–4. The pH value of the TME is weakly acidic, which is not beneficial

FIGURE 10 Cu-based NMs for combined PTT with RT. (a) CuS/

131

I-PEGDA/AIPH hydrogel for enhanced photothermal brachytherapy

T80-AuPt@CuS heterostructure for synergistic radio-photothermal therapy of breast cancer. Reprinted with permission from Cai

ZHONG ET AL.25 of 43

for OH generation. Therefore, developing more energetic and weakly acidic adaptable Fenton/Fenton-like agents with

high ROS productivity is a good way to enhance CDT.

By means of hyperthermia-induced elevated Fenton chemical reaction rates, ultrasmall BSA-CuFeS

NPs were pre-

pared via an ecofriendly biomineralization strategy for PTT and pH-independent CDT of breast cancer (Chen

et al., 2020; Chen, Luo, et al., 2019; Ruan et al., 2021; Tan et al., 2022). Interestingly, BSA-CuFeS

NPs could produce

comparable amounts of OH over wide pH ranges of 7.4, 6.5, 5.4, 4, and 3, indicating that the BSA-CuFeS

NPs dis-

played a pH-independent Fenton-like reaction. To explore the Fenton-like reaction mechanism, the dialysate was ana-

lyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES) at predetermined time intervals. In all

the different pH buffers, no obvious Cu ions could be detected, indicating that BSA-CuFeS

NPs integrally served as a

heterogeneous Fenton-like catalyst but not the released Cu ions to boost the production of OH. In addition, under

808-nm laser irradiation, the heat by BSA-CuFeS

NPs was able to further improve the OH-producing efficiency, which

synergistically favored the effective suppression of tumor growth. Moreover, BSA-CuFeS

NPs of 4.9 nm in size were

quickly cleared out of the body, effectively avoiding long-term and systemic toxicity. In addition to the simple synthesis

of CuFeS

NPs via a bioinspired albumin-mediated strategy, they could be formulated in situ from CuFe

NPs in

colon tumors full of H

S. As a proof of concept, CuFe

NPs were constructed as the precursor of CuFeS

, and upon

meeting endogenous H

S, CuFeS

NPs could be formulated in situ for PTT-CDT of colon cancer (Figure 11a; Liu, Liu,

Wan, et al., 2021). The tricky things about this work included three strategies: remodeling the reductive nature of TME

FIGURE 11 Cu-based NMs for combined PTT with CDT. (a) H

S-activated PTT-CDT of Cu

NPs by in situ sulfuration of

CuFe

American Chemical Society. (c) TRF-mCuGd hierarchical structure for Cu(I) self-supplying CDT with PTT for human breast cancer.

0.4

@PEG-RGD

nanostructures for CDT-enhanced PTT of melanoma, lung cancer, and human breast cancer. Reprinted with permission from Lyu

et al. (2020). American Chemical Society

26 of 43 ZHONG ET AL.

by depleting H

S, as well as increasing the amount of OH by hyperthermia and H

S accelerated valence conversion

between Fe

and Fe

ions. Thus, H

S-depleted CuFe

agents activated specific PTT and CDT for synergistic anti-

cancer effects, providing new insight for developing novel treatments for colon cancer.

In addition to modulating pH or redox properties, increasing the specific surface area has been reported to be

a highly efficient catalytic reaction in ROS generation (Zhuang et al., 2012). Inspired by this, hollow Cu

NPs

with abundant active sites were constructed for the photothermal-enhanced CDT of breast cancer (Wang, An,

et al., 2020). Compared with the solid Cu

NPs, the specific surface area of hollow Cu

NPs was substantially

improved from 19.027 to 33.100 m

1

,asrevealedbyBrunauer–Emmett–Teller (BET) analysis. To confirm the

better catalytic efficiency of hollow Cu

NPs,theelectronspinresonance(ESR)spectrumwasusedwith5,5-

dimethyl-1-pyrroline-N-oxide (DMPO) as the trapping agent of OH. The ESR spectrum suggested that hollow

exhibited a better chemodynamic performance at a higher temperature. Both in vitro and in vivo studies

further verified the synergistic therapeutic effect. Similarly, Cu

Se nanocubes with hollow structures were also

successfully prepared for PTT-CDT of breast cancer (Figure 11b; Wang, Zhong, et al., 2019). Compared with

NIR-I light, a 1064-nm laser located within NIR-II (1000–1350 nm) is capable of a higher penetration depth. Via

an anion exchange method with Cu

O nanocubes as the template, Cu

Se nanocubes were endowed with an opti-

mized PCE of 50.89% in a high NIR II window, which allowed excellent photothermal effects on 4T1 cells under

1064-nm laser irradiation for PTT. In addition, Cu

Se nanocubes showed a strong catalytic rate at pH 7.0, acting

as outstanding chemodynamic agents for CDT. Together, Cu

Se nanocube-mediated PTT-CDT achieved greatly

enhanced efficacy compared with PTT or CDT alone. Compared with other Cu-based NMs, Cu

Se nanomaterials

are particularly interesting due to the physiological effect played by trace elements of Cu and Se in the

human body.

For Cu-based CDT, the formation of Cu

, a highly efficient chemodynamic agent, is usually based on the redox

reaction between Cu

and GSH to initiate CDT. However, with the different interactions, the coordination process

between Cu

and GSH occurred much earlier than their redox process, thus leading to the insufficient generation of

ions. To provide enough Cu

ions, a highly efficient nanoplatform of a CuO dot-decorated Cu@Gd

hierarchical

core@shell structure was designed to self-supply Cu

ions for PTT-enhanced CDT of breast cancer (Figure 11c; Zhang,

Xie, et al., 2021). Under weakly acidic conditions, the copper oxide (CuO) dots (COD) in the shell were first dissolved to

release Cu

ions, followed by reaction with Cu

in the core to produce Cu

ions. Finally, with the coexistence of Cu

and H

, the Fenton-like reaction could be initiated for CDT. In addition, Cu@Gd

had broad absorption between

700 and 900 nm. Under 808-nm laser irradiation (0.8 W cm

2

), an excellent photothermal effect was achieved. Interest-

ingly, by western blot analysis, superoxide dismutase-1 (SOD-1) was activated by Cu@Gd

, leading to more H

generation for the Cu

-catalyzed Fenton reaction. In contrast, Cu@Gd

could also inactivate glutathione peroxidase

4 (GPX4), an important protein that works to eliminate intracellular ROS to maintain redox equilibrium. Therefore, the

inactivation of GPX4 further improved the accumulation of OH, further amplifying oxidative stress in MDA-MB-231

and MCF-7/DDP tumor cells. These results indicated that Cu@Gd

as a nanozyme that mimics the agonist of SOD-1

and the antagonist of GPX4, accelerated cell death.

In the strategy of photothermally enhanced CDT, the photothermal stability of PTAs should also be considered in

addition to the methods for improving Fenton chemistry. However, PTAs with high photothermal stability usually suf-

fer from difficulty in degradation. Conversely, PTAs with rapid degradation ability may not be good at photothermal

stability. Therefore, balancing the two conflicts of high photothermal stability and rapid degradation ability is a difficult

issue for the desired PTT-CDT of cancer. Considering that, BP was an inherent captor for Cu ions, after capture, the

interaction between BP and Cu ions killed two birds with one stone. Surface Cu

ions enhance the photothermal sta-

bility of BP-based PTAs but accelerate the degradation of BP via redox reactions. Based on this theory, Cu

ions were

tightly captured by BP nanosheets (BPNS) via coordination and electrostatic attraction. Forming BP@Cu

nanostructures for complementary PTT and CDT of melanoma, lung cancer, and human breast cancer under 808-nm

laser irradiation (Figure 11d; Lyu et al., 2020). Similar to the abovementioned Cu

Se nanocubes, both P as the

macroelement and Cu as the trace element are necessary for human health, and this unique biosafety shows the clinical

potential of BP@Cu-based PTAs.

Cu-based NMs showed outstanding catalytic performance in Fenton-like reactions by reducing the reliance on

low pH, accelerating the reaction rate by PTT, and modulating the TME of self-supplying H

and GSH depletion.

Additionally, considering their good biocompatibility and biodegradability, they have potential in future

cancer CDT.

ZHONG ET AL.27 of 43

4.1.5 | Combination of PTT with SDT

SDT, with advantages in overcoming the drawbacks of PDT, shows broad and promising application in combating can-

cer. However, as a kind of ROS-based dynamic therapy, SDT efficacy also highly relies on O

assistance since it plays a

vital role in transforming into

and O



. To supply sufficient O

for enhanced SDT, herein, Janus composed of the

hollow semiconductors CuS and Pt (Pt-CuS) was successfully synthesized to load tetra-(4-aminophenyl) porphyrin

(TAPP) for PTT-augmented SDT of colon cancer (Figure 12; Liang et al., 2019). In this design, hollow CuS with a large

inner cavity functioned not only as the DDS for TAPP delivery but also as PTA for PTT under 808-nm laser irradiation.

By depositing Pt, the photothermal performance of CuS was significantly enhanced due to the effect of the local electric

field enhancement. Moreover, Pt also possessed catalase (CAT)-mimicking activity by decomposing endogenous H

to O

for hypoxia relief. Importantly, 808-nm laser-irradiated Pt-CuS could further accelerate the catalytic activity of Pt

to elevate the O

level, thus facilitating SDT efficacy. Upon further coating with a thermally sensitive copolymer named

poly(oligo(ethylene oxide) methacrylate-co-2-(2-methoxyethoxy) ethyl methacrylate (p-(OEOMA-co-MEMA)),

temperature-responsive TAPP release could be realized. In vivo synergistic PTT-SDT almost completely eliminated the

tumors without obvious reoccurrence at a highly safe dose.

In principle, both US and NIR light could disturb the integrity and enhance the permeability of cell membranes via

thermal effect-based lipid arrangements. In some cases, photothermal agents could also mediate US-excited ROS pro-

duction, bestowing the convenience of operating combined PTT and SDT. Similar to SDT and RDT, Cu-based NMs have

rarely been reported to act as both PTAs and sonosensitizers, which limits their application in combined PTT–SDT.

4.1.6 | Combination of PTT with gene therapy

Despite the success of nanomaterial-based anticancer therapy in one solid tumor mimicking a “primary tumor”, tumor

metastasis is the main reason for the decline in survival rates. Therefore, complete containment of the primary tumor

FIGURE 12 Cu-based NMs for combined PTT with SDT. Hollow PCPT Janus architecture for synergistic PTT-SDT of colon cancer.

28 of 43 ZHONG ET AL.

in its early stages and timely suppression of tumor metastasis would improve the survival of patients. However, the syn-

chronous inhibition of primary and metastatic tumors is still a challenging task.

Based on the theranostic nanoplatform, this task would be solved for improved survival rates. PTT, as a local treat-

ment modality, is powerful in destroying the cell membrane structure and degenerating nuclear DNA, RNA, and pro-

teins of primary tumors. For example, CuS NPs have attracted immense interest for the PTT of tumors (Nikam

et al., 2020). For the inhibition of cancer metastasis, genetherapyhasbeenproventobeaneffectivemethodamong

various newly developed methods (Gilam et al., 2016). Gene therapy is mainly divided into DNA therapeutics and

RNA therapeutics, with the former including plasmid DNA (pDNA), oligodeoxynucleotides, and DNA aptamers and

the latter including miRNA, siRNA, ribozymes, and circular RNAs (Mirza & Karim, 2021). However, DDSs-mediated

gene delivery suffers from limited transfection efficacy and poor gene manipulation duetoinadequatecellular

uptake. Fortunately, hyperthermia could improve the targeting of nucleotides to the nucleus by loosening the cell

membrane. Taking advantage of individual PTT and gene therapy, a synergistic antitumor effect would be achieved

via their interplay. Herein, CuS nanoparticles complexed with plasmid DNA-encoding hypermethylation in cancer

1 (pDNA-HIC1) were entrapped by a dendrimer, forming RGD-CuS DENPs/pDNA polyplexes for simultaneous

photothermal-gene therapy of breast cancer (Figure 13; Ouyang et al., 2021). With RGD navigation, CuS NPs generat-

ing heat significantly delayed tumor growth under 1064-nm laser irradiation. Moreover, the delivered pDNA-HIC1

could inhibit cancer cell invasion and metastasis in a serum-enhancing manner via upregulated expression of HIC1,

a tumor suppressor gene, by methylation that could be promoted in triple-negative breast cancer (TNBC). In vivo

FIGURE 13 Cu-based NMs for combined PTT with gene therapy. RGD-CuS DENPs/pDNA polyplexes directed combined PTT/gene

ZHONG ET AL.29 of 43

studies demonstrated that NIR light-irradiated RGD-CuS DENPs/pDNA polyplexes effectively inhibited primary

tumor and lung metastasis for prolonged survival. Cu-based NMs are easily prepared to increase the transfection effi-

ciency of genes by manipulating physical and chemical properties, showing promise in highly effective PTT-gene

therapy against cancer.

4.1.7 | Combination of PTT with immunotherapy

PTT by NIR light irradiating localized tumors can stimulate the host's immune system by causing the release of tumor

antigens after tumor cell apoptosis and necrosis, which in turn promotes antigen presentation to T cells to induce a dis-

tal effect. However, PTT alone does not efficiently control tumor metastasis and recurrence just by activating the host's

immune system because different tumor cells can escape recognition and response of the immune system via specific

inhibitory signaling pathways.

Cancer immunotherapy has become a research hotspot and has achieved tremendous progress in recent decades. At

present, including four types of immune checkpoint blockade (ICB) therapy, cytokine therapy, cancer vaccines, and chi-

meric antigen receptor (CAR)-T cell therapy, immunotherapy has exhibited encouraging clinical responses in some

lucky patients (Chen, Chen, & Liu, 2019). However, the abovementioned strategies suffer from many shortcomings,

including low clinical objective response rates, risk of causing autoimmune diseases, off-target side effects, cytokine

release syndrome, and complicated manufacturing processes with extremely high costs. By learning from each other's

strengths, there is great hope that combining PTT with immunotherapy would make cancers curable in the years to

come. Immune checkpoints, with the negative regulatory ability of immune activation to make tumors immune-resis-

tant, limit antitumor responses with unprecedented rates of long-lasting tumor responses in patients. Considering that

many immune checkpoints, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell

death 1 (PD-1), are initiated by ligand–receptor interactions, they can be blocked by antibodies or modulated by recom-

binant forms of ligands or receptors, forming ICB therapy (Pardoll, 2012). Herein, with the aid of the outstanding

hyperthermic performance of CuS NPs, anti-PD-L1-mediated ICB was combined with CuS NP-PEG-Mal-based PTT for

breast cancer (Figure 14a; Wang, He, et al., 2019). In this study, CuS NPs not only contributed to the thermal ablation

of tumors for PTT but also worked as an antigen-capturing agent to adsorb and transport antigens released during

hyperthermia to DCs for immune activation by surface modification of maleimide PEG (PEG-Mal). Moreover, with

anti-PD-L1 administration, both primary and distant tumors showed significantly slower growth. In another study, CuS

NPs were also used with PD-1 blockade for photothermal ablation and immune remodeling of triple-negative breast

cancer (TNBC) (Figure 14b; Cheng et al., 2020). The differences compared with the above work contain three points.

First, with dendritic large-pore mesoporous silica nanoparticles (DLMSNs) as the DDSs, CuS NPs were deposited in situ

inside the large pores of DLMSNs, and the immune adjuvant resiquimod R848 could be loaded. Second, the 4T1 cell

membrane homogenously covered the surfaces of DLMSNs to improve the homing ability to tumors and conjugation

with peptides. Third, the anti-PD-1 peptide of AUNP-12 was linked by an acid-labile benzoic-imine bond consisting of

PEG. After step-by-step preparation, the final functional AM@DLMSN@CuS/R848 was applied to holistically treat met-

astatic TNBC. Under 980-nm laser irradiation, hyperthermia was generated, followed by tumor antigen generation,

increased R848 release, weakly acidic TME responsive AUNP-12 detachment, all these changes synergistically exerted

tumor vaccination, and T lymphocyte activation to prevent TNBC recurrence and metastasis.

In addition to ICB, cytokine therapy as a chief participant in regulating immune responses also shows promise in

cancer immunotherapy. Cytokines participate in regulating the survival, activation, and differentiation of T cells.

Inflammatory cytokines such as interleukin 1β(IL1β), IL2, IL12, IL18, tumor necrosis factor α(TNF-α), and interferon-

γ(IFN-γ) can promote innate and adaptive immune responses, playing a positive role in fighting against immune resis-

tance (Wang & Mooney, 2018). Among these cytokines, IL-12 can interact with other members of the immune system.

It has been reported that IL-12 promotes not only type 1 helper T (Th1) cell differentiation and the proliferation of natu-

ral killer (NK) cells and cytotoxic T lymphocytes (CTLs) but also the secretion of IL-2, TNF-α, IFN-γ, granulocyte-

macrophage colony-stimulating factor (GM-CSF), perforin, and granzyme B, systematically enhancing antitumor

immune responses. However, fetal adverse effects appeared with systemic administration of IL-12, but intratumoral

injection of the IL-12 gene exhibited many superiorities of sustained local expression and sustained effective concentra-

tion of local IL-12 compared with direct delivery of recombinant IL-12 protein. Considering these facts, mesoporous

SiO

was chosen as the DDSs for PTA/gene codelivery to realize CuS-based NIR-II PTT and in situ cytokine therapy

through local generation of IL-12 (Figure 14c; Lin et al., 2021). In the CSP@IL-12 nanocomplex, SiO

was

30 of 43 ZHONG ET AL.

functionalized with poly((2-di-methylamino)ethyl methacrylate) (PDMAEMA) to have positive charges. Then, plasmid

DNA encoding the IL-12 gene with negative electrons was attracted to realize in situ expression of the recombinant IL-

12 protein. Combined with 1064-nm laser irradiation, antitumor photoimmunotherapy was systemically improved.

In addition, clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR associated 9 (Cas9) technol-

ogy has been combined with CuS NPs for photothermal immunotherapy (Guo et al., 2014). Cu-based NM-mediated

hyperthermia also controls the expression of several thermosensitive gene elements, such as the HSP promoter, for

enhanced PTT immunotherapy (Sun, Zhang, et al., 2021).

4.2 |Chemotherapy-based combined cancer therapy

Insufficient drug accumulation in tumor cells is the major cause of chemotherapy failure. Although the strategy of

DDSs-assisted chemotherapeutics has shown promise in delivering enhanced drug contents, only 0.7% of the

FIGURE 14 Cu-based NMs for combined PTT with immunotherapy. (a) CuS NPs-PEG-Ma with anti-PD-L1 for combined PTT and ICB

(b) AM@DLMSN@CuS/R848 biomimetic nanoplatform for PTT and immune remodeling of TNBC. Reprinted with permission from Cheng

ZHONG ET AL.31 of 43

administered NMs could truly arrive at the solid tumor (Wilhelm et al., 2016). Therefore, it remains a great challenge to

improve the targeting ability of chemotherapeutics via localized on-demand release, controlled release, and other

routes, including combination with other treatments, to improve the therapeutic effect.

In this regard, a metal-drug coordination nanoplatform of Cu-TG was developed to achieve efficient treatment of

breast cancer via CDT-chemotherapy (Yuan et al., 2020). Ingeniously, 6-thioguanine (6-TG), as a chemotherapy drug

with abundant N and S, could act as the ligand to bond Cu ions, forming Cu-TG with a high drug loading rate (60.1%)

and 100% utilization rate. Moreover, the sulfhydryl group of 6-TG guaranteed the coexistence of Cu

/Cu

, which endo-

wed Cu-TG with multiple nanozyme performances. First, Cu-TG with glutathione peroxidase (GSH-Px)-like activity could

deplete GSH to trigger the release of 6-TG and Cu ions, thereby enhancing the T

relaxation rates of Cu ions for T

weighted MRI and chemotherapy. Second, upon entering tumor cells, the released Cu

ions, as Fenton-like agents, could

react with endogenous H

to efficiently produce OH for CDT, showing horseradish peroxidase (HRP)-like activity.

Moreover, O

could also be generated under this condition, making Cu-TG highly efficient catalase (CAT)-like activities.

Based on the above properties, Cu-TG exhibited self-reinforcing circular catalysis for synergistic therapeutic outcomes.

Despite the multifunctional nanozyme performance of Cu-TG, the insufficient content of H

inside tumor cells was not

solved in this work. Glucose oxidase (GOx), a kind of natural oxidoreductase, has been proven to be an excellent H

producer due to its high catalytic capacity against β-D-glucose for adequate glucose supply. Herein, for improved

CDT-chemotherapy of breast cancer, an H

self-supplying nanoplatform was prepared through the one-step, biomi-

metic mineralization method. Using PEG-modified GOx as a template, copper-doped calcium phosphate (CuCaP) NPs

could be anchored; further loading with DOX successfully produced biodegradable DOX-loaded CuCaP (PGC-DOX;

Figure 15a; Fu et al., 2021). In this intelligent nanotheranostic, the shortcomings of GOx, including poor stability, short

in vivo half-life, and systemic toxicity, could be significantly reduced by biomineralization. In addition, CaP could sponta-

neously decompose to Ca

and PO

43

, which participate in normal metabolism under acidic TME triggering. After the

collapse of CaP, the cargos in PGC-DOX were consequently released, with GOx exhausting O

and supplying H

for

starvation therapy (ST); Cu

ions depleting GSH to activate H

self-reinforcing and GSH depletion amplified CDT;

and DOX for chemotherapy. Taken together, the prepared PGC-DOX realized cooperative cancer therapy by integrating

the three functions.

DDSs that can improve the drug contents in targeted tumors highly rely on the enhanced permeability and retention

(EPR) effect. To amplify the EPR effect for more drug accumulation, physical or pharmacological approaches, including

light/US irradiation and vasodilators, have been proven effective in elevating the endocytosis of NMs (Dhaliwal &

Zheng, 2019). Moreover, these external stimuli can also provide precise spatiotemporal control of drug release at desired

sites of interest. Among various vasodilators, some gases, such as NO and CO, which are endogenous gas transmitters,

are capable of augmenting the EPR effect via vasodilation (Szabo, 2016). Consequently, to achieve US/gas-mediated

CDT-chemotherapy enhancement, hybrid AIBA@FeCuS-FeCO NPs with DSF were fabricated for gas-chemo-

chemodynamic therapy of orthotopic gastric tumors (Figure 15b; Sun, An, et al., 2021). This nanoplatform could

enhance cancer therapy through four different pathways. First, upon US irradiation, the thermal effect could trigger the

decomposition of thermally responsive 2, 20-azobis(2-methylpropionamidine) dihydrochloride (AIBA) into N

and alkyl

radicals, with N

further driving AIBA@FeCuS-FeCO degradation, thus eliciting alkyl radical-induced cytotoxicity inde-

pendent of O

. Second, the generated alkyl radicals induce the decomposition of the CO donor of Fe

(CO)

, releasing

CO for vasorelaxation to enhance the EPR effect. Third, the alkyl radicals would also break up FeCuS into Fe

and

ions, and with Fe

interaction with H

,OH-mediated CDT would lead to ferroptosis. Fourth, the released

chelates with DSF, forming CuL

for cancer therapy. By virtue of precise spatiotemporal control, good US-

activated multimodal therapies were realized.

Docetaxel (DTX), a traditional chemotherapeutic drug, was found to decrease the proportion of myeloid-derived

suppressor cells (MDSCs) and induce MDSC transformation from an M2-like phenotype to an M1-like phenotype

(Millrud et al., 2018). M1-type macrophages are desired because they can produce both proinflammatory cytokines and

inducible nitric oxide synthase (iNOS) to kill cancer cells. In contrast, M2-type macrophages promote tumor angiogene-

sis. Therefore, DTX can not only kill cancer cells but also polarize tumor-associated macrophages (TAMs). For breast

cancer, immunotherapy is usually functionally limited owing to “cold tumors”characterized by low PD-L1 expression

and CTL infiltration but high levels of MDSCs that are resistant to the immune system (Galon & Bruni, 2019). From

the perspective of DTX in modulating the tumor immune microenvironment, herein, DTX-loaded nanocomposites of

FA-CuS/DTX@PEI-PpIX-CpG, denoted FA-CD@PP-CpG, were designed for synergistic phototherapy and DTX-based

chemotherapy-enhanced immunotherapy of breast cancer (Figure 15c; Chen, Zhou, et al., 2019). In this nanoplatform,

CuS, a famous PTA, and protoporphyrin IX (PpIX), a widely used PS, could be excited by 808- and 650-nm laser for heat

32 of 43 ZHONG ET AL.

and

generation-based PTT and PDT, respectively. Moreover, on the one hand, the level of CTL infiltration was pro-

moted; on the other hand, MDSCs were effectively polarized toward the M1 phenotype, and these regulatory effects

contributed to the enhanced efficacy against breast cancer. Moreover, further combined with anti-PD-L1 antibody-

based ICB, these nanocomposites offered efficient efficacy in inhibiting breast cancer.

Cu-based NMs have shown excellent anticancer activity by acting as DDSs, multistimuli responsive sensitizers, and

catalysts for chemotherapy, radiotherapy, thermal therapy, and dynamic therapy, showing the potential of these

nanostructures in future cancer treatment.

FIGURE 15 Cu-based NMs for chemotherapy-based combined cancer therapy. (a) Nanocatalytic PGC-DOX with H

self-supply and

Wiley-VCH GmbH. (b) AIBA@FeCuS-FeCO with DSF for US-activated gas-chemo-chemodynamic therapy of orthotopic gastric tumors.

WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

ZHONG ET AL.33 of 43

4.3 |Other forms of synergistic cancer therapy

Encouraged by various kinds of Cu-based NMs in different types of treatment modalities, some other synergistic thera-

pies worth mentioning will be introduced in this section. ROS-based dynamic therapy relies heavily on the TME due to

the harsh conditions of hypoxia and high content of reductive GSH, which are not harmful for ROS generation and

accumulation. A nanoagent that can respond to both high-tissue penetrated external stimuli and in situ internal chemi-

cal energy for ROS generation, accompanied by TME modulation ability, would be more attractive in cancer therapy.

By simply synthesizing intermetallic compounds (IMCs) via a one-step solvothermal method, PtCu

nanocages were

uniformly synthesized for GSH depletion-amplified sono-chemodynamic therapy of breast cancer (Zhong

et al., 2020). Under US irradiation, PtCu

nanocages as inorganic sonosensitizers could produce two types of ROS,

including

and OH, due to the partial formation of Cu

O, a kind of PS on their surface. In addition, due to the

existence of Cu

,PtCu

nanocages could mimic peroxidase (POD), functioning as Fenton-like agents for CDT by

highly generating OH. Interestingly, they as nanozymes could also mimic GSH-Px, depleting 3 mM GSH only by

0.1 mM PtCu

nanocages and 0.1 mM H

, showing outstanding performance in the potential of GSH-depleted ROS

accumulation.Bothinvitroandinvivostudiesdemonstrated a significant growth delay, showing promise in

nanozyme-based cancer therapy.

With research interest focusing on microwaves (MWs), Prof. Meng's group developed exogenous stimulation of

MW-mediated microwave dynamic therapy (MDT) and microwave thermal therapy (MWTT) for cancer therapy.

MW-excited ROS generation for MDT shows an outstanding advantage that it can achieve deep tumor treatment

without interference from gas and bone. Similar to PSs and sonosensitizers, microwave sensitizers are also indispens-

ableforMDTs.Forexample,theydevelopedPEG-IL-LM-ZrO

SNPs for ROS generation by transferring electrons

from Ga to the surrounding H

OandO

. However, this sensitizer-mediated MDT still faces some challenges. First,

the quantum yield of ROS generation needs to be improved. Second, ROS-induced cell death and vascular occlusion

prompt surviving tumor cells to secrete vascular endothelial growth factor (VEGF), facilitating the metastasis and

recurrence of tumors. Finally, the sufficient accumulation of microwave sensitizers at the tumor should also be

considered.

Based on the above challenges, the construction of MDT sensitizers that can meet the above requirements is badly

needed. Herein, they designed red blood cell (RBC) membrane-coated ZrO

@CuO/Cu-MOF-apatinib-PCM (RBC-

Zr@APC/C) NPs for effective MWTT–MDT- chemotherapy of breast cancer (Figure 16a; Chen, Wu, et al., 2021). In this

study, mesoporous hollow ZrO

nanospheres were first fabricated via the template-sacrifice method. Then, as a truck,

they codelivered CuO/Cu-MOF, tetradecanol (PCM), and apatinib to the tumors. Finally, by covering with immune-

escape RBCs for stealth, this sensitizer could be highly internalized by tumor cells. Upon MW irradiation, Zr@C/C NPs

could produce O

and O



,OH and

, especially O



, for hypoxia-relieved MDT-MWTT (MWDTT). In addition,

blocked apatinib will be released from the mesoporous shell due to the MWTT-induced switch of PCM in a

temperature-controlled manner. Apatinib, as an antiangiogenic drug, significantly downregulated the expression of

VEGF and platelet endothelial cell adhesion molecule (CD31), thus inhibiting tumor angiogenesis after MWDTT. This

study further expanded the application of Cu-based NMs in combined cancer therapy.

In recent years, gas therapy (GT) using several gaseous molecules (e.g., NO, CO, H

S, N

, and H

) with physiological

modulation functions has emerged as a promising field for cancer therapy (He, 2017). The underlying mechanism of

GT was largely due to interference with tumor cell metabolism. Compared with normal cells, the “Warburg effect”

appears in cancer cells with energy consumption via a glycolysis route rather than via the aerobic respiration method.

These gases maintain bioenergetic homeostasis to block the survival pathway for cancer cells while protecting normal

cells, showing an anti-Warburg effect. Therefore, GT for cancer has been considered far superior to traditional thera-

pies. Among them, small gas molecules of H

with inert and life element properties endow hydrogen therapy with

exceptional treatment performance (Wu et al., 2019). However, direct delivery of H

by DDSs from outside the body

would not transport enough H

into tumors due to its low solubility and high diffusivity. Therefore, developing NM-

based gas generators in stimuli-responsive ways would improve the efficacy of gas targeting ability. Herein, an NIR

light-driven H

-releasing donor of NaGdF

:Yb,Tm/g-C

/Cu

P (UCC) was encapsulated with zeolitic imidazolate

framework-8 (ZIF-8), forming UCNPs/g-C

/Cu

P@ZIF-8 NPs (UCCZ NPs) for H

-mediated cascade-amplifying GT–

PTT–PDT–CDT of breast cancer (Figure 16b; Wang, Ji, et al., 2020). Due to the acid responsibility of the ZIF-8 shell and

folate receptor-mediated endocytosis, CSNPs could be selectively engulfed by tumor cells to release UCC. Under

980-nm laser irradiation, NaGdF

:Yb,Tm (UCNPs) could emit purple and blue light, which in turn excited g-C

generate e



in the conduction band (CB) and excited Cu

P to generate h

in the valence band (VB), respectively.

34 of 43 ZHONG ET AL.

Generally, e



and h

will quickly recombine via the Z-scheme pathway, thus maintaining the stronger oxidizability of

in the VB of g-C

and the higher reducibility of e



in the CB of Cu

P. Moreover, the generated strong oxidizing

in the VB of g-C

could be reduced by GSH in the TME, thus providing isolated e



in the CB of Cu

P to reduce

O for H

production via in situ water splitting-mediated gas therapy. In this process,

and O



could also be pro-

duced for PDT via energy or e



transfer to O

. At the same time, Cu

P could not only dominate PTT but also act as a

GSH-activated Fenton-like agent for photothermally enhanced CDT (ECDT). Significantly, the four types of treatment

modalities were not mutually independent. In detail, both PDT- and CDT-mediated oxidative stress would induce the

expression of stress proteins that would make cancer cells tolerate heat effects from PTT. Fortunately, H

can inhibit

the expression of these stress-induced proteins, making ROS-based PDT/CDT more effective in combination with PTT.

In addition, GSH depletion by h

in the VB of g-C

or Cu

in Cu

P would further enhance PDT. Collectively, the

four synergetic GT–PTT–PDT–CDT treatment modes were realized in a H

-mediated cascade amplification process.

Advanced tumors are skilled in dysregulating, hijacking, and depleting immune-related cells, cytokines, and mole-

cules to escape immune surveillance and elimination by immune cells. Although ICB therapy benefits a small subset of

patients, this reality of “cold”tumors makes immunotherapy feel quite helpless. Turning tumors from “cold”to “hot”

would improve the responsiveness of tumors to ICB. Immunogenic RT, PDT, CDT, and chemotherapy have been uti-

lized as immunomodulatory adjuvants to augment ICB. As a hallmark of many cancers, high serum levels of estradiol

(E2) directly affect cell proliferation, cell cycle arrest, and ultimately tumorigenesis (Revankar et al., 2005). From

FIGURE 16 Cu-based NMs for other synergistic therapies. (a) RBC-Zr@APC/C NPs for microwave dynamic thermal therapy and

generated

UCCZ-FA for cascade-amplifying synergetic hydrogen therapy–PTT–PDT–CDT of breast cancer. Reprinted with permission from Zhang,

O@CaCO

nanocomposites with

anti-CD47 antibody for synergistic PTT–PDT–CDT–CIT–immunotherapy of colorectal cancer. Reprinted with permission from Chang

ZHONG ET AL.35 of 43

clinical experience, hormone therapy has been widely used in estrogen receptor-abundant tumors. Interestingly, in the

presence of Cu

-based catalysis, estrogens with DNA will form stable adducts while generating ROS. This phenome-

non could be embezzled to conduct ROS-based cancer therapy by supplying additional Cu

to tumors. Herein, Cu

ions were coordinated with 5,10,15,20-tetrabenzoatoporphyrin (H

TBP) ligands, forming a nanoscale metal–organic

framework (nMOF) of Cu-TBP. Additionally, with an anti-PD-L1 antibody, synergistic PDT-CDT-ICB of melanoma and

ovarian carcinoma was achieved (Figure 16c; Ni et al., 2019). In this design, Cu

ions catalyzed E2 metabolism to gen-

erate OH, O



, and H

for E2-induced CDT and radical therapies via the Cu-E2 catalytic redox cycle, whereas LED

light-triggered H

TBP generated

and Cu-TBP generated O



-mediated PDT. In vivo studies showed that B16F10

and SKVO-3 tumors with high E2 levels were sensitive to Cu-TBP-mediated CDT/PDT. Further combined with α-PD-

L1, a strong abscopal effect was observed in the bilateral B16F10 tumor model. This clever combination broadened the

therapeutic effects of CBI on hormonally dysregulated tumor phenotypes.

Ion interference therapy (IIT), originating from the discovery of the clinically common phenomenon of “calcifica-

tion”in certain tumor types after RT or chemotherapy, has been proven to induce cancer cell death by altering the

metal content balance, including ferroptosis and calcicoptosis (Zhang et al., 2019). Calcium overload-based IIT was

named Ca

interference therapy (CIT). As weak acidity is the typical hallmark of tumors, many Ca

ion-releasing

NMs, including CaO

and CaCO

, have been reported for CIT (Dong, Feng, Hao, et al., 2020; Zhang et al., 2019). For

example, a Cu

O@CaCO

@HA (CCH) nanostructure was combined with an anti-CD47 antibody for colorectal cancer

(CRC) “turn-on”therapy via synergistic PTT-PDT-CDT-CIT immunotherapy (Figure 16d; Chang et al., 2020). Under

the specific physiological feature of H

S overexpression in CRC, the pH-triggered decomposition of CaCO

would lead

to the release of Ca

ions for CIT and the core of Cu

O for the following functions. Hereafter, with H

S sulfuration,

O transformed into metabolizable Cu

nanocrystals for strong NIR light (1064 nm)-irradiated PTT, PDT and

enhanced CDT. Furthermore, in combination with CD47 blockade (anti-CD47), protumoral M2 TAMs could be polar-

ized to the tumoricidal M1 phenotype, reprogramming the immunosuppressive TME to initiate T cell-mediated

immune responses. Therefore, CCH as a TME-triggered “turn-on”therapeutic tool was successfully constructed for the

precise targeted therapy of specific CRCs.

5|CONCLUSIONS AND PERSPECTIVES

Cu-based NMs have attracted increasing attention not only in biomedical communities due to their easily modulated

nanostructure and versatile composition but also have high therapeutic properties and imaging functions in the bio-

medical field due to their unique physicochemical properties and biological effects. Therefore, in this review, we sys-

tematically summarized the recent application progress of Cu-based NMs in cancer imaging and tumor therapy. For

cancer imaging, PA imaging, PET imaging, and multimodal imaging based on Cu-based NMs were summarized, as well

as strategies to improve the diagnostic effectiveness. Next, the application of Cu-based NMs in cancer treatment was

introduced, which was mainly divided into monotherapy and combination therapy. Although the application of Cu-

based NMs in tumor imaging and therapy has achieved remarkable achievements and progress in the past few years,

there are still some intractable problems and challenges that need to be overcome to achieve clinical translation.

First, the biosafety of Cu-based NMs needs to be systematically evaluated. The traditional view is that Cu, as a tran-

sition metal element, is more toxic than Fe or Mn, so the application of Cu-based NMs in biomedicine is relatively lim-

ited. Fortunately, the as-prepared Cu-based NMs have good biocompatibility and biosafety, which solves the important

toxicity problem of Cu in biomedicine. Notably, the prerelease of Cu ions from Cu-based NMs should be avoided prior

to exerting therapeutic properties to avoid potential toxicity. However, the long-term retention of Cu-based NMs in vivo

can raise toxicity concerns. Therefore, it is very challenging to prepare ultrasmall or biodegradable Cu-based NMs for

cancer theranostics.

Second, it is necessary to develop Cu-based NMs with high photothermal performance and light penetration ability.

Due to the scattering of light in the tissue, its penetration depth is low, so it can only treat diseases on the surface of the

skin and has limited therapeutic effects on deep-seated diseases. Through precise modulation of the nanostructure,

composition, and physicochemical properties, the photothermal conversion efficiency of Cu-based NMs is enhanced,

and the photoresponse wavelength has been extended to the second NIR biological window, thereby effectively enhanc-

ing the penetration of light into the tissue penetration depth. In addition, the combination of PTT and other treatment

modalities can achieve the effect of synergistic treatment, which further overcomes the problem of low treatment effi-

ciency caused by the low tissue penetration ability of phototherapy.

36 of 43 ZHONG ET AL.

Third, the large-scale fabrication and surface engineering of Cu-based NMs need to be addressed to meet the

requirements of clinical translation. At present, the preparation of Cu-based NMs is still in the laboratory stage, and

there are still many problems in large-scale production, which need to be given more attention in the future.

Last, it is of great significance to prepare Cu-based NMs with modulated TME properties. The complex TME impairs

the therapeutic performance of Cu-based NMs, although some Cu-based NMs have also been reported to have the abil-

ity to modulate the TME, mainly focusing on depleting GSH and reacting with H

to generate OH for CDT, but these

materials alone are not sufficient for high-efficiency tumor treatment.

Most importantly, if these bottlenecks are successfully overcome, the therapeutics of Cu-based NMs will lead to sig-

nificant progress in clinical application. We believe that Cu-based NMs will become highly competitive and promising

multifunctional nanomaterials for cancer imaging therapy in the future.

ACKNOWLEDGMENTS

This work was supported by the Basic and Clinical Cooperative Research and Promotion Program of Anhui Medical

University (2021xkjT028), the Open Fund of Key Laboratory of Antiinflammatory and Immune Medicine (KFJJ-

2021-11), Grants for Scientific Research of BSKY from Anhui Medical University (1406012201), a Jiangsu Natural Sci-

ence Fund for Young Scholars (BK20210730), and the Postdoctoral Science Foundation of China (2021M702383).

CONFLICT OF INTEREST

The authors have declared no conflicts of interest for this article.

AUTHOR CONTRIBUTIONS

Xiaoyan Zhong: Writing –original draft (lead). Xingliang Dai: Writing –original draft (equal). Yan Wang: Resources

(equal). Hua Wang: Supervision (equal). Haisheng Qian: Supervision (equal). Xianwen Wang: Conceptualization

(lead); funding acquisition (lead); supervision (lead); writing –review and editing (supporting).

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this review.

ORCID

Xiaoyan Zhong https://orcid.org/0000-0003-4725-6452

Xianwen Wang https://orcid.org/0000-0002-6343-440X

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AUTHOR BIOGRAPHIES

Xiaoyan Zhong, PhD, received her PhD degree from Huazhong University of Science and Technology

(HUST) in 2020, and then joined the Department of Toxicology in School of Public Health, Suzhou

Medical College of Soochow University as a Postdoctor. Her research interest is the development and

biosafety assessments of multifunctional inorganic nanomaterials for applications in reactive oxygen

species-based cancer theranostics.

Xianwen Wang, PhD, obtained his PhD degree under the guidance of Prof. Liang Cheng and

Prof. Zhuang Liu in the Institute of Functional Nano & Soft Materials (FUNSOM) at Soochow

University in 2021. Then he joined Anhui Medical University as a specially-appointed professor

and doctoral supervisor. His current research interest is the development of multifunctional

nanomaterials for biomedical application.

How to cite this article: Zhong, X., Dai, X., Wang, Y., Wang, H., Qian, H., & Wang, X. (2022). Copper-based

nanomaterials for cancer theranostics. WIREs Nanomedicine and Nanobiotechnology, e1797. https://doi.org/10.

1002/wnan.1797

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Nov 2020
ACS NANO

Specific cytotoxicity for catalytic nanomedicine triggered by the tumor microenvironment (TME) has attracted increasing interest. In this work, we prepared AgBiS 2 hollow nanospheres with narrow bandgaps via rapid precipitation in a weakly polar solvent, which lowered the intrinsic energy gap for the active production of highly reactive hydroxyl radicals (• OH), especially in the TME. The as-prepared AgBiS 2 hollow nanospheres exhibited enhanced optical absorption and high photothermal conversion efficiency (44.2%). In addition, the hollow structured AgBiS 2 nanospheres were found to have a peroxidase-mimicking feature to induce cancer cell-specific cytotox-icity while exhibiting negligible cytotoxicity toward normal cells, which might be attributed to the efficient production of highly reactive • OH originating from the overexpression H 2 O 2 in the TME caused by surface catalysis. In particular, the cancer cell-specific cytotoxicity of the nanospheres was greatly enhanced both in vitro and in vivo upon irradiation with a near-infrared (NIR) laser (808 nm). The above-mentioned features of the hollow structured AgBiS 2 will make it a promising candidate for tumor therapy.

Intercalation‐Activated Layered MoO3 Nanobelts as Biodegradable Nanozymes for Tumor‐Specific Photo‐Enhanced Catalytic Therapy

Article

Jan 2022

The existence of natural van der Waals gaps in layered materials allows them to be easily intercalated with varying guest species, offering an appealing strategy to optimize their physicochemical properties and application performance. Herein, we report the activation of layered MoO3 nanobelts via aqueous intercalation as an efficient biodegradable nanozyme for tumor‐specific photo‐enhanced catalytic therapy. The long MoO3 nanobelts are grinded and then intercalated with Na+ and H2O to obtain the short Na+/H2O co‐intercalated MoO3 nanobelts (NH‐MoO3). In contrast to the inert MoO3 nanobelts, the NH‐MoO3 nanobelts exhibit excellent enzyme‐mimicking catalytic activity for generation of reactive oxygen species, which can be further enhanced by the photothermal effect under a 1064 nm laser irradiation. Thus, after bovine serum albumin modification, the NH‐MoO3 nanobelts can efficiently kill cancer cells in vitro and eliminate tumors in vivo facilitating with 1064 nm laser irradiation.

Bimetallic oxide Cu1.5Mn1.5O4 cage-like frame nanospheres with triple enzyme-like activities for bacterial-infected wound therapy

Article

Apr 2022
NANO TODAY

Copper-based nanomaterials with intrinsic enzyme-like activity have shown increasing potential as new broad-spectrum antibiotics. However, due to its low catalytic activity, poor glutathione (GSH) depletion capacity, and complex material design, their feasibility is still far from satisfactory. Herein, bimetallic oxide Cu1.5Mn1.5O4 cage-like frame nanospheres (CFNSs) were successfully prepared by a two-step approach for the first time, including gas-assisted soft template solvothermal preparation of Cu-Mn hydroxide hollow sphere (Cu-Mn-OH HSs) precursors, and then calcination to synthesize Cu1.5Mn1.5O4 CFNSs. This ingenious, simple, and rapid material synthesis strategy could obtain well-dispersed and extremely uniform Cu1.5Mn1.5O4 CFNSs with a special mesoporous cavity structure, making its performance close to the requirements of practical applications. Interestingly, the as-prepared Cu1.5Mn1.5O4 CFNSs showed enhanced triple enzyme-like activities (oxidase-, peroxidase-, and glutathione peroxidase-like), which could significantly promote the generation of reactive oxygen species (ROS) due to the increased exposure of active edge sites. Cu1.5Mn1.5O4 CFNSs could effectively kill bacteria by combining OXD-like, POD-like, and GSH-Px-like nanozyme activities. More importantly, in vivo wound healing showed that Cu1.5Mn1.5O4 CFNSs could be conveniently used for wound disinfection. In addition, Cu1.5Mn1.5O4 CFNSs exhibited excellent biosafety without observable toxicity or side effects in mice. This work emphasizes the potential application of bimetallic oxides with triple enzyme-like activities in antibacterial therapy.

Multidimensional transitional metal-actuated nanoplatforms for cancer chemodynamic modulation

Article

Mar 2022
COORDIN CHEM REV

Cancer is one of the deadliest diseases threatening human health worldwide. As the understanding of the tumor microenvironment (TME) becomes more comprehensive, many promising TME-enabled nanotherapies have been developed, such as dynamic therapy and immunotherapy. Transitional metal elements also play an indispensable regulatory role in TME by exerting crucial physiological functions in the human body, thereby affecting the formation and progression of tumors, and exhibiting significant potential for anticancer strategies. They can spontaneously activate in situ chemical regulation at the tumor site based on the Fenton/Fenton-like reaction to interfere with the TME redox potential. Based on this, the concept of chemodynamic therapy (CDT) as one of the most popular therapeutic methods came into being. This article introduces the transitional metal-based chemodynamic adjustment mechanisms and systematically reviews the latest CDT-relevant antineoplastic nanosystems, with their applications based on different dimensions. Finally, the opportunities and challenges of transitional metal-based chemodynamic modulation strategies in future development and clinical translation are examined.

Self-sufficient copper peroxide loaded pKa-tunable nanoparticles for lysosome-mediated chemodynamic therapy

Article

Feb 2022
NANO TODAY

Chemodynamic therapy (CDT) has recently gained much attention for Fenton chemistry-mediated cancer treatment, but the anti-tumor efficacy of CDT suffers from insufficient amount of endogenous H2O2 and inefficient decomposition of metal oxides to catalytic ions. Although tremendous progress has been made to increase the amount of H2O2 in the tumor region, the antitumor activity of CDT remains limited due to the suboptimal ionization to release enough amounts of catalytic ions for converting endogenous H2O2 to reactive oxygen species (e.g. highly toxic hydroxyl radical ·OH). Here, a series of nanoparticles with tunable acid dissociation constant (pKa) values from 5.2 to 6.2 were prepared to load H2O2 self-supplying copper peroxide, which can be used to trap copper peroxide in acidic lysosome to produce ample catalytic ions that convert self-supplied H2O2 into ·OH by a robust Fenton reaction. The highly reactive ·OH effectively permeate the lysosomal membrane through lipid peroxidation and thus kill tumor cells in a lysosome-mediated manner. Most importantly, the Fenton reaction is processed inside the lysosomal compartment, which avoids the cytoplasmic antioxidants such as glutathione (GSH) to scavenge ·OH. Overall, this work provides a new strategy to enhance CDT efficacy.

Copper‐based nanomaterials for cancer theranostics

Abstract

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