Nano‑mediated strategy for targeting and treatment of non‑small cell lung cancer (NSCLC)

Abstract

Lung cancer is the most common type of cancer, with over 2.1 million cases diagnosed annually worldwide. It has a high incidence and mortality rate, leading to extensive research into various treatment options, including the use of nanomaterial-based carriers for drug delivery. With regard to cancer treatment, the distinct biological and physico-chemical features of nano-structures have acquired considerable impetus as drug delivery system (DDS) for delivering medication combinations or combining diagnostics and targeted therapy. This review focuses on the use of nanomedicine-based drug delivery systems in the treatment of lung cancer, including the use of lipid, polymer, and carbon-based nanomaterials for traditional therapies such as chemotherapy, radiotherapy, and phototherapy. The review also discusses the potential of stimuli-responsive nano-materials for drug delivery in lung cancer, and the limitations and opportunities for improving the design of nano-based materials for the treatment of non-small cell lung cancer (NSCLC).

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Naunyn-Schmiedeberg's Archives of Pharmacology
https://doi.org/10.1007/s00210-023-02522-5
REVIEW
Nano‑mediated strategy fortargeting andtreatment ofnon‑small cell
lung cancer (NSCLC)
SumelAshique1· AshishGarg2· NeerajMishra3· NehaRaina4· LongChiauMing5,6,7· HardeepSinghTulli8·
TapanBehl9· RadhaRani4· MadhuGupta4
Received: 3 February 2023 / Accepted: 4 May 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Lung cancer is the most common type of cancer, with over 2.1 million cases diagnosed annually worldwide. It has a high
incidence and mortality rate, leading to extensive research into various treatment options, including the use of nanomaterial-
based carriers for drug delivery. With regard to cancer treatment, the distinct biological and physico-chemical features of
nano-structures have acquired considerable impetus as drug delivery system (DDS) for delivering medication combinations
or combining diagnostics and targeted therapy. This review focuses on the use of nanomedicine-based drug delivery systems
in the treatment of lung cancer, including the use of lipid, polymer, and carbon-based nanomaterials for traditional therapies
such as chemotherapy, radiotherapy, and phototherapy. The review also discusses the potential of stimuli-responsive nano-
materials for drug delivery in lung cancer, and the limitations and opportunities for improving the design of nano-based
materials for the treatment of non-small cell lung cancer (NSCLC).
Keywords Nanoparticles· Non-small cell lung cancer (NSCLC)· Polymeric nanoparticles· Stimuli-responsive
nanoparticles
Introduction
Non-small cell lung cancer (NSCLC) remains the leading
cause of cancer-related deaths. The complexity and hetero-
geneity of NSCLC make it difficult to diagnose and treat,
leading to a need for ongoing research to better understand
the disease. The use of nanotechnology-based tools has
resulted in significant improvements in clinical outcomes
for NSCLC through retrospective studies of traditional
therapies (García-Fernández etal. 2020; Ferlay etal. 2017).
Lung cancer (LC) will surpass breast cancer as the next
highly detected cancer worldwide in 2020 with two mil-
lion new cases. However, lung cancer is the primary reason
of death worldwide due to its 1,796,144 fatalities, which
accounts for 18% of the total 9,958,133 deaths caused by
cancer. Even though smoking is the chief causing factor
for lung cancer, geography and racial differences have a
big impact on how often the disease occurs (Stabile etal.
* Madhu Gupta
madhugupta98@gmail.com
1 Department ofPharmaceutics, Bharat Institute
ofTechnology (BIT), School ofPharmacy, Meerut250103,
UP, India
2 Department ofPharmaceutics, Guru Ramdas Khalsa Institute
ofScience andTechnology, Jabalpur, M.P483001, India
3 Amity Institute ofPharmacy, Amity University Madhya
Pradesh, Gwalior474005, MP, India
4 Department ofPharmaceutics, School ofPharmaceutical
Sciences, Delhi Pharmaceutical Sciences andResearch
University, PushpVihar, NewDelhi110017, India
5 Department ofPharmacy Practice, Faculty ofPharmacy,
Universitas Airlangga, Surabaya60115, Indonesia
6 School ofMedical andLife Sciences, Sunway University,
47500SunwayCity, Malaysia
7 PAPRSB Institute ofHealth Sciences, Universiti Brunei
Darussalam, Gadong, Brunei, Darussalam
8 Department ofBiotechnology, Maharishi Markandeshwar
Engineering College, Maharishi Markandeshwar (Deemed
toBe University), Mullana, Ambala133207, India
9 School ofHealth Sciences andTechnology, University
ofPetroleum andEnergy Studies, Bidholi, Dehradun, India

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2017; McIntyre and Ganti 2017). There are primarily two
types of lung cancer—non-small cell lung cancer (NSCLC)
and small cell lung cancer (SCLC). Basically 15% of lung
cancers are categorized under SCLC, a fatal tumor, while
approximately 80–85% of lung cancers are NSCLC in the
form of squamous cell carcinomas, large cell carcinomas,
and adenocarcinomas (Roca etal. 2017). This particular kind
of lung cancer may develop in non-smokers as well, despite
smoking being the primary risk factor (Sun etal. 2007).
The middle of the lung is where squamous cell lung can-
cer often develops from the proximal bronchi. It frequently
contributes to 25 to 30% of NSCLC and can manifest in
smokers (Socinski etal. 2016). Adenomas and squamous
cell lung carcinomas progress more rapidly than large cell
lung carcinomas, which may develop anywhere in the lung
tissue. Large cell carcinoma makes up around 3% of all lung
malignancies, although it has a much lower overall survival
rate than the other subtypes (Seong etal. 2020). Chemo-
therapy, targeted therapy, immunotherapy, surgery, and
radiation therapy are currently available treatment options
for NSCLC. A huge number of patients under clinical stages
Ib-IV require systemic therapies (chemotherapy, targeted
therapy, or immunotherapy) (Rochigneux etal. 2020). In
general, cisplatin- or carboplatin-based doublet platinum-
derived chemotherapy is the first-line treatment for NSCLC
(Pai-Scherf etal. 2017). Small-sized EGFR tyrosine kinase
inhibitors (EGFR-TKIs) such as erlotinib and gefitinib have
recently been introduced as the 2nd-generation therapy for
the management of NSCLC (Lynch etal. 2004). EGFR-TKIs
have minimal toxicity and considerably enhance quality of
life when compared to the conventional chemotherapy regi-
men. The most current EGFR-TKI, osimertinib, has been
routinely employed as first-line treatment for individu-
als having progressed EGFR-mutant NSCLC since it was
approved in April 2018 (Zhou and Zhou 2015). Nanomedi-
cine is a subfield of nanotechnology that uses substances
with a size range of 5 to 200nm for medical and health
applications (Chen etal. 2017a). By increasing anticancer
drugs’ stability and bioavailability, facilitating cancer target-
ing across biological membranes, expanding circulation and
plasma concentration, minimizing enzyme deterioration, and
minimizing their toxic effects and antigenicity, a nanoparti-
cle drug delivery system (NDDS) used in nanomedicine has
the capabilities to resolve the disadvantages of anticancer
drugs (Choi and Han 2018). Through an improved perme-
ability besides enhanced permeation and retention (EPR)
effect, nanoparticles are also useful for accelerating the
accumulation of therapeutic drugs in cancer tissues. (Bør-
resen etal. 2020). Only a few of the numerous kinds of nano-
particles created for the administration of anticancer drugs
have advanced to the clinical stage (Garbuzenko etal. 2019).
To our surprise, nanomedicine—which combines treatment
and diagnostics—has developed into a workable paradigm
for cancer treatments. It provides the best targeting potential
and extremely efficient nanocomposites to carry cargo when
coating them with targeted moiety (i.e., ligand, peptide, anti-
bodies) for imaging and therapeutics. The concept led to the
creation of several nanoparticles that are ideal for both diag-
nosis and drug administration, accelerating the development
of customized medicine (Fernandez-Fernandez etal. 2011).
Nanomedicine has made it possible to create multifunctional
systems that can both help with diagnosis and deliver treat-
ments with greater precision to the target spot or tissue.
Here, we examine how nanotechnology is being applied to
the management of NSCLC. Furthermore, combining drug
delivery strategies depending upon the extrinsic stimulation
and tumor microenvironment (TME) through other chemo-
therapeutic and/or immune-modulatory therapies may have
synergistic benefits in lung cancer treatment. In the near
future, numerous innovations will be required to design the
most efficient, intelligent, and smart DDS techniques for the
management of lung cancer.
Lung cancer: anoverview
“Small cell lung cancer (SCLC) and non-small cell lung
cancer (NSCLC)” are the two primary subtypes of lung
cancer (Fig.1). Even though SCLC is less frequent than
NSCLC, it is more aggressive. Big cell lung cancer, squa-
mous cell carcinoma, and adenocarcinoma are the three pri-
mary histological subtypes of NSCLC. Again, each subtype
is distinct and responds to available treatments in a different
way. The interplay of ecological factors, including cigarette
smoke, and genetic predisposition affects lung carcinogen-
esis. Infrequent germ line transformations such as “epider-
mal growth factor receptor (EGFR), retinoblastoma, and
p53” prominently enhance the risk of developing cancer.
Decreased DNA healing effectiveness can correspondingly
be a substantial aspect in the development of lung cancer.
According to reports, chemicals in tobacco smoke are highly
involved in lung cancer development. Tyrosine kinases are
clearly implicated in lung cancer pathogenesis, according
to new research. Cancer may develop as a result of constitu-
tive kinase activation, downstream signaling, overexpres-
sion, and autocrine paracrine stimulation. Tyrosine kinase
oncogenic activation, such as that of MET, PIK3CA, and
EGFR is often seen in NSCLC and presents a therapeutic
target (Burstein and Schwartz 2008; Paul and Mukhopad-
hyay 2004). Notwithstanding advances in “non-small cell
lung cancer (NSCLC) treatment,” the last 5-year survival
rate for carcinogenic progression has increased by fivefold in
the past few months. Surgical procedure is a crucial compo-
nent of treating diseases in their early stages. However, lung
cancer surgery is complicated and can have negative effects.
Another obstacle to patients receiving good treatment for

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lung cancer is early diagnosis of lung malignant develop-
ment. Most lung disease patients will have advanced tumor
stages when they are detected, and about 75% of these indi-
viduals will have symptoms. Radiation therapy and cancer
chemotherapy are relatively successful in the early stages of
NSCLC treatment. With the advent of large-scale genome-
wide association studies and the availability of precise
sequencing tools, it is now obvious that molecular hetero-
geneity occurs especially inside tumor subgroups. Hetero-
geneity between the initiating malignancy and its metastatic
counterpart may occur, even among the tissues of particular
cancer, or depending on the tissue that initially gave rise to
the tumor. The variety of tumor cells’ genetic composition,
as well as their propensity to gain adaptive tolerance, makes
developing an efficacious treatment difficult (Jamal-Hanjani
etal. 2017). A new technique that addressed the biochemical
particularities of each participant is required.
Nanomedicine asanalternative theranostics
Nanotechnology, which has been utilized to treat and diag-
nose a number of biological disorders, is one of the rapidly
increasing subjects in biomedical research. Nanotechnology
has witnessed a tremendous surge in its usage in treating a
variety of ailments in recent years for instance, cancer, dia-
betes, bacterial infections, cardiovascular disease, and others
(DiSanto etal. 2015). Because traditional therapy techniques
for lung cancer have significant drawbacks, researchers and
scientists have concentrated on creating nanoscale chem-
otherapeutic drugs using delivery systems that include
polymeric nanoparticles, liposomal nanoparticles, metal
nanoparticles, inorganic nanoparticles, and biointegrated
nanoparticles. The number of nanostructures is depicted in
Fig.2, which are commonly employed in tumor targeting.
Because of their small dimension, the nanoparticles have
been shown to be efficient theranostic agents for treating
lung cancer. This allows them to preferentially concentrate
in tumor cells owing to an “EPR effect.” Furthermore, nano-
particles have a significant drug loading capacity owing to
their large surface area to volume ratio and accessibility of
functionalization (Mukherjee and Patra 2016; Ashique etal.
2022a). Because of their increased biocompatibility and
ability to evade renal clearance, nanoparticles outperform
Fig. 1 Lung cancer: types and
ration of SCLC and NSCLC
Fig. 2 Nanoparticles used in drug delivery and tumor targeting

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traditional medicinal procedures. Because they have exhib-
ited diverse characteristics including diagnostics imaging,
sensing, and treatments, researchers may employ a range of
nanoparticles for several applications in lung cancer thera-
nostics. The diversified applications of various nanocarrier
systems are explained in Fig.3. This study concentrated on
theranostic uses of a range of nanocomposite types that have
demonstrated immense ability to be used in the therapeutic
based as well as detection of lung cancer that included (i)
polymeric nanoparticles, (ii) liposomal nanoparticles, (iii)
metal nanoparticles; (iv) bio-nanoparticles (Ashique etal.
2022b).
Routes ofadministration ofNDDS forNSCLC
It has been difficult to deliver a novel drug delivery sys-
tem (NDDS) for lung-related disorders, but it has a lot of
potential. The literature contains several reports of attempts
to identify the most effective strategy, path, resource, and
method for achieving the intended treatment objectives.
In general, regional (inhalation) or systemic (intravenous)
administration can be used to deliver medication specifi-
cally to the lungs. The preferred delivery strategy, systemic
administration, has a number of limitations, including toxici-
ties on healthy cells and an effective drug concentration at
the site of tumor (Lee etal. 2015. Localized delivery is still
preferable since it reduces the possibility of adverse effects
brought on by systemic dispersion. The drug administration
via inhalation is beneficial and promising for both its local
and potential systemic effects, when drug molecules may
get gather in the lymphatic circulatory system after admin-
istration (Mangal etal. 2017). A NDDS may decrease the
toxicities associated with pharmaceuticals by encapsulating
them suggesting that a novel drug delivery approach may
also have the potential to minimize the widespread toxic-
ity of medications like doxorubicin (Roa etal. 2011) and
cisplatin (Devarajan etal. 2004), when they are delivered
through the pulmonary route. It is probable that the pulmo-
nary administration of NDDS and the EPR effect are incom-
patible. Further research has been done on an active targeted
approach for NDDS lung delivery. According to research
accomplished by Tseng and his coworkers, the “bEGF-dec-
orated” nano-system has proficiently absorbed by/interacted
with tumors overexpressed with EGFR found in animal stud-
ies, and large dosages of cisplatin were effectively adminis-
tered to the malignant lung cells (Tseng etal. 2009.) There
are particular issues that must be taken into consideration
in order to ensure that NDDS is adequately administered
to the lungs. The design of the pulmonary mechanism as
well as the lung clearing process may make it more difficult
to accumulate a substantial measure of drug-encapsulated
NDDS at the site of tumor (Razak etal. 2021). The size
of NDDS is concerning because nanometer-sized particles
are generally expelled during normal breathing. The appro-
priate construction of nanostructures is also necessary to
enable the collection as well as distribution of the drugs
they carry on cancerous cells while preventing damage to
normal cells. This minimizes the risk of complications while
increasing the efficacy of the treatment. Numerous methods
have reportedly been researched, including pH-triggered
medication discharge from NDDS (Joshi etal. 2014). Under-
standing the microenvironment is essential for developing a
successful NDDS for tumor targeting, in lung cancer.
Nanomedicine‑based treatment strategy
forNSCLC
Their function and consequent therapeutic effects are largely
determined by the functionalization of nanoparticles as well
as their geometry and materials (Shi etal. 2017a). Addi-
tionally, by altering these characteristics, it is conceivable
to employ them as contrast agents for PET or CT imaging
procedures, effectively creating dual theranostic platforms
(Li etal. 2016a). For a variety of NSCLC treatments, numer-
ous nanocarrier systems are really being evaluated as pro-
spective medication delivery strategies. Lipidic, polymeric,
and metal-based nanoparticles are the competent classes of
nanocarriers that are extensively researched for lung cancer.
The use of ACE-2 and nanotechnology in the treatment of
NSCLC was discussed in a prominent publication by
Sivalingam and Singh (2023). The most common, deadly,
and severe subgroup of NSCLC is “lung adenocarcinoma and
squamous cell carcinoma (SCC).” It often develops in scar
tissues with regions of persistent irritation toward the lung’s
periphery. It has a low mortality rate of fewer than 5% and a
Fig. 3 Biomedical applications of nanoparticles

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greater amount of genetic alteration. (Dong etal. 2020)
ACE-2 levels are higher in SCC than in healthy tissue
regardless of the stage of the malignancy. It has been
suggested that “DNA methylation,” which functions as a
cancer regulator, is the cause of elevated ACE-2 expression
(Zhang etal. 2020). Samad etal. demonstrated that ACE-2
is upregulated in lung adenocarcinoma and squamous cell
carcinoma, with ACE-2 suppressing mortality in “human rat
alveolar epithelial cells,” lowering cell migration, and
mitigating NSCLC (Samad etal. 2020). In another study,
Kim et al. (2022), investigated the antitumor and
immunological modulatory properties of the “scL-RB94
nanocomplex” in experimental models of “human non-small
cell lung cancer (NSCLC).” Mice with human NSCLC
tumors were given systemic therapy with “scL-RB94,” which
dramatically reduced tumor development by boosting death
and reducing cancer cell development invivo. Treatment
with scL-RB94 also improved antitumor immune function
by increasing immunological identification markers and
attracting innate immune cells like natural killer (NK) cells
(Kim etal. 2022). The “NSCLC cell line H460” was used to
investigate the efficacy of “anti-Bcl-xL siRNA” included in
an “EGFR-targeted nanomedicine with scFv ligands
(NM-scFv)” created by Nguyen and his colleague. “Anti-
EGFR scFv ligand”–modified nanostructure was
demonstrated to enable active gene transport into “H460
cells” and resulted in roughly 63% of genes being silenced at
both the mRNA and protein levels and concluded that “anti-
Bcl-xL NM-scFv” variant enhanced the apoptotic activity of
cisplatin (Nguyen etal. 2022). Polymeric micelle loaded with
paclitaxel for treatment for NSCLC was created by Lu and
his group in 2022. They discovered the first indication that
“Pm-Pac (polymeric micelle-paclitaxel)” may have extended
overall survival in NSCLC patients without pleural
metastases while maintaining a favorable safety profile.
Overall, this research presents a fresh viewpoint on how
nanomedicine is being developed to examine chemotherapy
effectiveness (Lu etal. 2022). For the purpose of delivering
therapeutic “p53-mRNA” into “p53-null hepatocellular
carcinoma (HCC) and non-small cell lung cancer (NSCLC)
cells,” Cerami etal. (2012) constructed self-assembling lipid-
polymer hybrid nanoparticles. Thirty-six percent of
individuals with HCC and 68% of those with NSCLC had
defects in the p53 tumor suppressor gene (Cerami etal.
2012). The nanostructures were suggested as effective
methods for enhancing macrophage-mediated phagocytosis
by Moradinasab etal. 2022. In the interest of achieving an
improved antitumor activity in the management of NSCLC,
the current study proposes CAR-macrophage as the cutting-
edge method and it acts as a bridge between the innate and
adaptive immune systems (Moradinasab etal. 2022). Kim
etal. investigated whether p53 genetic therapy delivered by
a cancer-targeting nanostructure (called SGT-53) can
supplement anti-programmed cell death-1 (PD-1)
immunotherapy, allowing it to be used in non-responding
patients. Utilizing syngeneic mouse models of lung
malignancies that are resistant to anti-PD-1, they establish
that reinstatement of natural p53 expression stimulates
anti-PD-1 to reduce cancer development and extend the
lifespan of malignant cells bearing animals. The findings
showed that SGT-53 can improve efficient immune function
toward NSCLC by lowering immunosuppression chemicals
and immunosuppressive cells (M2 macrophages and
regulatory T cells) (Kim etal. 2022). In a similar study by Lu
and his researcher group, polymeric micellar paclitaxel-based
nanoparticle’s antitumor activity was investigated in both
“A549/H226 cells and A549/H226-derived xenograft tumor
models.” (Lu etal. 2023) For the treatment of NSCLC,
inhibiting “YAP expression” may be a promising therapeutic
strategy. Huang etal. (2022) developed a “nano-cocktail”
treatment method described by using “amphiphilic and block-
dendritic-polymer-based nanoparticles (NPs)” for tailored
co-delivery of “EGFR-TKI gefitinib (Gef) and YAP-siRNA”
to produce a controlled treatment against NSCLC (Huang
etal. 2022). According to Das and his researcher group,
polyphenol-based tailored nanostructures have shown to bind
with a wide range of protein domains and cellular signal-
transduction pathways, having a significant impact on key
cellular functions. Nano-constructed dietary polyphenols
have a number of molecular processes and potential
therapeutic targets for the treatment of lung cancer (Das etal.
2022). Shukla etal. (2022), planned to create and evaluate
“nintedanib-loaded niosomes” as inhalable carriers for
increasing their therapeutic effectiveness by site-specific drug
deposition against NSCLC. Invitro tests showed that
nintedanib-loaded niosomes had much greater cytotoxicity,
which was further supported by 3D spheroids (Shukla etal.
2022). In a similar way, “Indomethacin-loaded liposomes”
were created by Sarvepalli etal. (2022) for the successful
management of NSCLC. The 3D spheroid experiment results
showed that “IND-Lip” nano-conjugate performed noticeably
better in exvivo tumor reduction (Sarvepalli etal. 2022). For
the dual delivery of “pemetrexed disodium (PMX) and
siRNA” for the treatment of NSCLC, Xiaoyu etal. (2023),
created “poly-glutamic acid-modified cationic liposomes
(γ-PGA-CL).” The recent research demonstrated the viability
of combining “PMX and siRNA via γ-PGA-CL” as a feasible
therapy method for NSCLC after invivo antitumor trials
from the complex group significantly inhibited tumor
development (Xiaoyu etal. 2023). In order to combat
NSCLC, Dominguez-Martinez and his colleague created
“folate-decorated cross-linked cytochrome-C nanoparticles.”
The findings show that both invitro and invivo, the NPs
significantly inhibited the development of tumors in
cancerous cells that exhibited FR overexpression
(Dominguez-Martinez etal. 2022). Thangavelu and his group

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created liposomes that were loaded with “6-gingerol” for the
evaluation of its anti-NSCLC therapeutic effectiveness in
both invitro and invivo. Whenever compared to “standard
Gn, lipo-pharmacological Gn’s” characteristics were
considerably enhanced in “BALB/c mice” that had NSCLCs
generated. “Lipo-Gn” can therefore be taken into
consideration for its expanding uses against lung cancer
(Thangavelu et al. 2022). In a similar manner,
“amentoflavone-loaded nanoparticles” were created by Zhao
etal. (2022) to target NSCLC. The remarkable drug carrying
efficiency, excellent water tolerance and dispersion, extended
bioavailability, and pH-dependent release of the “AMF@
DOX-Fe3 + -PEG nanoparticles (ADPF NPs)” which is the
“coordination of ferric ions (Fe3 +), amentoflavone (AMF),
PEG-polyphenol, and doxorubicin (DOX).” ADPF NPs
resulted in targeted drug delivery and improved drug
deposition in the cancer site. Furthermore, by lowering the
“aldo–keto reductase family-1B10 (AKR1B10)” activity, the
ADPF NPs might prevent the development of the A549
tumor and improve the cardiotoxicity caused by free DOX.
This nanoplatform that is combined with AMF and DOX
offers a wide range of potential applications in the treatment
of clinical tumors (Zhao etal. 2022). For the treatment of
NSCLC, Patil and his colleague created “inhalable
bedaquiline (BQ)–loaded cubosome (BQLC) nanocarriers.”
Upon nebulization, the “BQLC nanocomposites” displayed
good aerodynamic qualities. After 48h of administration, the
“BQLC” demonstrated increased cytotoxicity toward NSCLC
(A549) cells compared to plain BQ. Moreover, research using
3D tumor simulations shows that cubosomal nanocarriers are
more effective in fighting cancer than free BQ (Patil etal.
2021). Another study for the treatment of NSCLC was
achieved by the development of quercetin-loaded micelles by
Li etal. (2022). The confluence of “enhanced permeability
and retention (EPR) and active targeting impact” may be
responsible for the good tumor targeting capabilities and
anticancer effectiveness shown by quercetin-loaded
PEGMA–PDMAEA–PCL/DSPE–PEG–biotin mixed
micelles (Que-MMICs). Together, Que-MMICs showed
improved anticancer effect in the NSCLC-harboring mouse
model and indicated substantial deposition at the tumor site
(Li etal. 2022). The “bevacizumab-coated gefitinib-loaded
nanoparticles (BCGN)” with dual-responsive drug release
were created by Zhao etal. (2023). These nanoparticles were
designed to suppress tumor growth and phosphorylation of
“epidermal growth factor receptor (EGFR).” Both the “A549
and the HCC827 human NSCLC models” show considerable
tumor growth inhibition when treated with a dual-responsive
release of the drugs “bevacizumab and gefitinib.”(Zhao etal.
2023) In another work, Asadollahi etal. (2022) created
nanostructured lipid carriers (NLCs) in order to assess the
synergistic anticancer effects of co-delivering “erlotinib
(ELT) and resveratrol (RES),” a naturally occurring phenol
derived from herbs, on NSCLC (Asadollahi etal. 2022). In
the subsections, they are briefly discussed. The targeting
strategy of nanoparticles toward NSCLC is explained in
Fig.4.
Liposomes
When natural or synthesized amphiphilic lipids are spread in
water, they spontaneously form vesicles with a bilayer shape
known as liposomes. Because of their biocompatibility and
advantageous safety profile, they have been extensively
researched as drug delivery vehicles ever since they were
created (Ashique etal. 2021). Phosphatidylcholine, choles-
terol, and other substances make up the bilayer structure of
liposomes, which are known to transport a variety of hydro-
phobic and hydrophilic big and small molecules for thera-
peutic purposes. Polyethylene glycol (PEG) can be grafted
onto their surface to change it, lengthening their half-life in
circulation (Moghimi and Szebeni 2003). In 1995 and 1999,
respectively, the FDA approved Doxil and Myocet, two of
the most popular doxorubicin-based liposomes (Barenholz
2012). Even though there are already sixteen liposomal
medications on the market, relatively few formulations are
approved as a type of treatment for NSCLC. Here, our group
enlisted current instances of liposomal formulations used for
therapeutic drug transport to the lungs. In 2014, Cheng etal.
used the new peptide GE11’s EGFR binding affinity to study
the liposomes’ size distribution (Cheng etal. 2014), and it
was discovered that 10% GE11 density in A549 cytotoxicity
was ideal. Cellular uptake tests also confirmed the clathrin-
mediated endocytosis pathway’s significant role. A dual-
ligand-modified triptolide-loaded liposome (dl-TPL-lip) was
created, for efficient triptolide (TPL) delivery to NSCLC via
pulmonary injection. An apoptosis assay was used to gauge
the ability to destroy cells (Lin etal. 2018). Importantly,
employing 3D tumor spheroids, the liposomes’ better tumor
Fig. 4 Tumor targeting strategy of nanoparticles against NSCLC

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penetration along with tumor growth suppression efficacy
was confirmed. For the treatment of NSCLC, Song etal.
(2017) developed a multifunctional targeting liposome in
2017 and got superior invivo results. Octreotide (OCT) was
used to decorate the liposome surface (Song etal. 2017).
Honokiol, which reduces tumor metastasis and inhibits the
creation of vasculogenic mimicking channels, and epiru-
bicin, an anticancer medication, were both co-encapsulated
in the liposome. These liposomes were found to be able to
downregulate PI3K, MMP-2, and MMP-9, while activating
caspase 3. Researchers from all across the world are paying
close attention to the pulmonary medication delivery tech-
nique, or local distribution via inhalation, as a viable option.
This necessitates the use of treatments with low doses of
low toxicity. In order to determine the effectiveness and side
effects of giving patients with lung metastases aerosolized
interleukin (IL)-2 liposomes. The liposome-aerosol was
inhaled three times daily for around 20min. On the basis
of earlier research, the dose was selected. Three cohorts of
three patients each received different doses of IL-2 three
times per day for a total of nine individuals. According to
researchers, inhaling IL-2 liposomes is safe and causes less
systemic damage (Skubitz and Anderson 2000). Aerosolized
liposomal cisplatin in patients with lung cancer showed that
cisplatin was well tolerated (Wittgen etal. 2007). Lowery
etal. designed doxorubicin encapsulated liposomal complex
engrafted with peptide molecules for targeted delivery of
drug into the malignancies site (Lowery etal. 2011). After
being labeled with Alexa Fluor 750, tagged liposomes were
used to follow the biodistribution in a murine Lewis lung
cancer model. Liposomes are often employed in lung cancer
theranostics because of their exceptional biocompatibility
and biodegradability (Sercombe etal. 2015). Additionally,
liposomes have an advantage over other nanoparticles since
they can easily be managed for sustained drug administration
and are effective for loading a large number of therapeutic
compounds (Bolhassani etal. 2014). Nanoliposomes often
experienced certain drawbacks, such as reduced stability and
high construction charges (Maja etal. 2020). IV drug deliv-
ery of liposome, having positively charged surface, has also
been shown to elevate liver enzymes and pro-inflammatory
cytokines in healthy C57BL/6 mice with efficient therapeutic
activity (Kedmi etal. 2010).
Polymeric nanoparticles
For the therapy of NSCLC, extensive research has been done
on polymeric nanoparticles using polymers for instance,
polycaprolactone (PCL), polylactic acid (PLA), and chitosan
(Esim etal. 2020). In addition to being widely available,
the properties of polymeric nanoparticles can be controlled
for steady as well as prolonged release, facile surface func-
tionalization, simple nano-sizing, freely available cellular
internalization, and the ability to enclose a wide range of
active compounds (including drugs, peptides, and oligonu-
cleotides) (Senapati etal. 2018). They are also more stable
in storage than lipid-based formulations. Despite this fact,
the complicated processing approach may make large-scale
manufacturing difficult. Nevertheless, numerous invitro
(lab-based experimental setup) and invivo (experiment
based on small animals) investigations have demonstrated
the non-toxicity of the PLGA nanoparticulate system, mak-
ing it excellent polymeric material for the therapy of NSCLC
(Semete etal. 2010). The main drawbacks of the drug deliv-
ery procedure, such as the harmful consequences of anti-
neoplastic therapy, have been addressed using polymeric
NPs (Singh and Nalwa 2007). They demonstrate an increase
in the effectiveness of chemotherapeutic and targeted treat-
ments by using polymeric NP to encapsulate hydrophobic
pharmaceuticals at large concentrations, extending circula-
tion duration, and improving transportation to the targeted
region (Allouche 2013). The FDA has authorized “Abrax-
ane®, an albumin-based nanocarrier” filled with paclitaxel
for the management of NSCLC and advanced breast cancer
(Ma and Mumper 2013). The use of “PEG-modified NPs”
that contain taxanes has been shown to increase the effec-
tiveness of combination chem-radiation treatment for non-
small cell lung cancer (Jung etal. 2012). Hu etal. presented
the effectiveness of “polycaprolactone nanoparticles” loaded
with paclitaxel in conjunction with “chronomodulated
chemotherapy” in the year 2017, (Hu etal. 2017) and they
also suggested a possible role for “circadian rhythms” in
tumor progression. Most significantly, Wang etal. revealed
intercellular translocation of NPs to cancer cell with invivo
suppressed primary cancer progression using mesenchymal
stem cells as a carrier to increase delivery of drug (pacli-
taxel) from NPs (Wang etal. 2019). “Crizotinib (for EML4-
ALK fusion–positive lung cancer) and polylactic tocopheryl
PEG 1000 succinate (PLA-TPGS)” were combined in a for-
mulation by Jiang etal. in 2015 that demonstrated sustained
release, caused cytotoxic effect in “NCIH3122 lung cancer
cells,” and detectable both early and late apoptosis (Jiang
etal. 2015). In the interest of overcoming resistance mecha-
nism, erlotinib was loaded onto PLGA. This method has
shown improved loading capacity, increased entrapment,
and prolonged release (Vaidya etal. 2019). Afatinib and
paclitaxel were placed into PLGA inhaled microspheres in
another trial. These NPs shown great biological compatibil-
ity, prolonged release, and maintained higher concentration
toward lung cells than other cell/tissue. These targeted NPs
are a suitable therapy for resistant lung cancer because of
all these benefits (Yang etal. 2019a). Lipid-based polymeric
micelles are a different class of nanoparticles; they are dis-
tinguished by an architecture that consists of a hydrophobic
core with the ability to transport medicines and a hydrophilic
PEG-shell. In South Korea and various European nations,

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“Genexol-PM,” a micelle formulation of “PLGA-b-methoxy-
PEG nanocarrier” carrying paclitaxel, has been authorized
for use in the treatment of cancer (Kim etal. 2007). Positive
anti-neoplastic outcomes were shown in a phase II study
with “Genexol-PM combined with gemcitabine” in those
suffering from advanced NSCLC; however, frequent level
III–IV toxicities were seen (Ahn etal. 2014). When added to
“PEG polymeric nanoparticles,” cisplatin has improved anti-
cancer activity toward cancer cells invitro (Li 2018). In the
treatment of NSCLC, co-encapsulated micelles encapsulat-
ing “itraconazole and paclitaxel” have shown reduced cyto-
toxicity (Zhang etal. 2018). Using modified micelles coated
with “a-conotoxin,” it is also able to deliver additional medi-
cations, such as “docetaxel,” to the A549 NSCLC cell line
(Mei etal. 2018). A new “polyurethane micelle” with prom-
ise for MRI diagnostic and chemotherapeutic treatment was
created by Ding and his group (Ding etal. 2014). As a poten-
tial remedy for drug resistance, the utilization of NPs in the
distribution of anticancer drugs has also been investigated.
In order to create biocompatible NPs that were extremely
efficient in resistant A549 cells and might suppress the pro-
duction of certain multidrug-resistance proteins, galactoxy-
loglucan and paclitaxel were utilized (Reshma etal. 2019).
Drugs containing polymeric NPs in the form of aerosols may
lessen cytotoxic effects (Abdelaziz etal. 2018). Significant
anticancer efficacy of cisplatin was reported in “A549 lung
adenocarcinoma cells” after lung injection of “gelatin-based
NPs.” (Elzoghby 2013) NPs of doxorubicin released from
polyisobutyl cyanoacrylate used for the treatment of mac-
rophages resulted in secondary cytotoxicity to lung cancer
cells after 8 and 24h (Al-Hallak etal. 2010). In a different
investigation, pulmonary administration of the hyaluronan-
cisplatin compound demonstrated enhanced lung drug con-
centration compared to intravenous cisplatin after 24h, with
reduced tissue/plasma ratio both in kidneys and the central
nervous system, lowering dose-limiting toxicities (Xie etal.
2010). Amreddy etal. created and assessed an NP approach
based on a “folic acid (FA)–coupled PAMAM-dendrimer-
polyethyleneimine” platform for the simultaneous delivery
of “cisplatin, siRNA, and human receptor-R” for the treat-
ment of lung cancer and they revealed that composite treat-
ment utilizing “FA receptor (FAR)”–targeted dendrimer
nanoparticles demonstrated precision and specificity toward
FAR–expressing cancer cells, improving the therapeutic
effectiveness and also reducing the cytotoxic effects against
healthy cells (Amreddy etal. 2018).
Nanostructured lipid carriers
Nanostructured lipid carriers are composed of emulsifier
dispersion in aqueous medium and partially liquid and
solidified solid lipids; nanoscale lipid particles are distrib-
uted (Makled etal. 2017). This loosely packed crystalline
structure permits drug molecule entrapment, lowers drug
leakage during storage, and permits regulated drug release
(Iqbal etal. 2012). Additionally, it has been discovered that
NLCs are distributed favorably in the organs, including the
lungs, which may enhance cancer therapy other than lung
cancer. The NLC system’s primary drawbacks are its limited
drug loading capacity (Poonia etal. 2016).
NLCs are considered as potential vehicles for the fab-
rication of efficient individualized cancer chemotherapy
therapies against NLC. These lipid-based nanoparticles
that are biocompatible and/or biodegradable have a core
matrix made of both solid and liquid lipids that is dissemi-
nated in a surfactant solution. Most hydrophobic cancer
treatments are more soluble in water after NLC. Their sur-
face modification can be employed to produce site-specific
tailoring for enhanced efficiency as well as for decreased
toxicities related to doses administered, which would help
cancer treatment overcome drug resistance. The necessity
of an early diagnosis in order to offer an appropriate prog-
nosis and treatment options justifies the significance of a
thorough lung cancer assessment. The first lung cancer
categorization was offered at the beginning of the twen-
tieth century, and it has been regularly updated to reflect
both the rise in cases and the discovery of new subgroups
of cell lung cancer (Travis etal. 2015). Many anticancer
moieties have so far been effectively created as NLCs. The
enhancement in the anticancer effectiveness of cytotoxic
medications with fewer side effects has been demonstrated
in preclinical research employing cell lines or animal mod-
els. Since they lack tumor selectivity characteristics, the
majority of cytotoxic medicines have a limited therapeutic
window that was previously indicated. The chosen dose
is extremely close to the maximum tolerated dose, which
makes it difficult to distribute the medication effectively.
NLCs have recently demonstrated tremendous potential
to target cancerous cells. Drug targeting that is passive or
active can target tumor cells (Torchilin 2011). NLCs were
recently designed to incorporate or connect multipurpose
compounds including anticancer drugs, antibodies as well
as ligands addressing MDR cancer cells, nucleic acids,
or P-gp inhibitors to block different MDR contributors.
The surface of MCF-7 cell line has overexpressed “breast
cancer resistance protein (BCRP),” which promotes higher
uptake of mitoxantrone hydrochloride (MTO) encapsulated
dextran-conjugated NLCs than basic drug solution (Zhang
etal. 2008, 2012). The exceptional drug uptake suggests
that drug efflux, which is mediated by the breast cancer
resistance protein (BCRP), has been inhibited. Docosahex-
aenoic acid (DHA)– and doxorubicin (DOX)–based NLCs
with the resistant “MCF-7/ADR” cell line also demon-
strated cytotoxicity at relatively low concentrations (16m
of doxorubicin and 112m of DHA) (Mussi etal. 2014).
Lipid nanoparticle carriers for bioimaging as well as for

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1 3
anticancer treatments that are loaded with camptothecin
and quantum dots were developed and tested by Hsu etal
(Hsu etal. 2013). Excellent fluorescence labelling of can-
cer cells was seen in invivo real-time tumor monitoring
using fluorescent imaging. In comparison to the free drug
solution, the produced theranostic NLC showed increased
cytotoxicity to the B16-F0 melanoma cell line and camp-
tothecin accumulations that were 6.4 times higher. For the
therapy of lung cancer, Patel etal. created DIM-CpPhC6H5
(DIM-P) and a tumor-homing PEGylated VEGF peptide
(CREKA peptide) encapsulated theranostic NLC sys-
tem (Patel etal. 2014). When compared to unconjugated
NLCs, the developed system showed a threefold increase
in attachment with protein molecules present in the tumor
plasma site. Studies revealed that CREKA peptide-con-
jugated designed systems moved through tumor vascula-
ture 40 times more than peptide-unconjugated NLCs. The
NLC-based theranostic preparation of MgO NPs (manga-
nese oxide nanoparticles) loaded with MMP2 cleavable
peptide and cancer-targeting compound exhibited superior
deposition inside the tumor and improved the MRI sign-
aling (Patel etal. 2014; Savla etal. 2014). Remarkable
antitumor effectiveness was seen invitro with the BRAF
(gene) inhibitor vemurafenib, which has been loaded
into NLCs using Chinese hamster ovary cells (CHOK1),
human lung (A549), ovarian (A2780), and melanoma
(COLO 829) cancer cells, as well as invivo using vari-
ous cancer models. The development of well-organized
means for delivering foreign genes, including siRNA or
DNA, to tumor cells is a key component of gene therapy
techniques. Recently, there has been a lot of interest in the
potential of NLCs as a means of delivering genes (Xue
and Wong 2011; Han etal. 2014a). The human lung cell
line (A549 cells) invitro cell viability study demonstrated
more than 80% of cell viability against control. Shao and
his colleague constructed paclitaxel (PTX)–loaded trans-
ferrin (Tf) NLCs (Shao etal. 2015). Invitro cytotoxicity
study illustrated more than fourfold decline in the IC50
value especially in comparison with PTX solution in lim-
iting the viability of carcinoma cells, taking into account
the maximum antitumor activity. Furthermore, the system
demonstrated high invivo and invitro gene transfection
efficacy. Similar to this, Chen etal. developed multifunc-
tional NLCs for simultaneous DNA and temozolomide
(TMZ) delivery (Chen etal. 2016). In an invitro cytotox-
icity research using U87MG cells, the formulation showed
over fourfold decrement in IC50 value compared to plain
temozolomide, indicating that malignant glioma cells have
the strongest anticancer effects. NLCs have several bene-
fits as a potential delivery system for genetic material (i.e.,
DNA) with their increased transfection proficiency, such
as lower cytotoxic nature along with higher gene loading
efficiency (Han etal. 2016).
Solid lipid nanoparticles
Colloidal nanocarriers called solid lipid nanoparticles
(SLNs) circumvent the problems associated with liposomes,
emulsions, etc. (Naseri etal. 2015). The medication is either
embedded within the solid core of SLNs or is positioned on
the exterior portion of the solid lipid that makes up SLNs.
They are less susceptible to enzyme breakdown than other
nanostructured systems, can resist mild pressure (such as
nebulization), and are biocompatible (Duan etal. 2010).
Additionally, the technology does not need organic sol-
vents, which makes it easier to pilot scale-up production
and gives the enclosed chemotherapeutic drug improved pro-
tection (Mishra etal. 2018). Unfortunately, the SLNs share
the problem of inadequate drug entrapment with other col-
loidal systems. SLNs are recently developed substitutes for
conventional colloidal delivery systems. SLNs demonstrate
substantial potential for drug localization and retention at the
actionable site via both passive and active targeting owing
to their unique abilities to encapsulate hydrophilic as well
as hydrophobic payloads in conjunction with nucleic acids
and proteins. For sustained and precise medication and gene
delivery, SLNs promise new vistas. Polymeric nanoparticles
and liposomes are combined in SLNs, which avoids both
acute and long-term toxicity (Scioli Montoto etal. 2020;
Chen etal. 2017b). The biocompatible lipids in SLNs,
which the body and lungs find bearable, were thought to
contribute to their superior safety profile (Dolatabadi etal.
2015). They are therefore highly advised for the delivery
of pulmonary drugs, whether in the form of suspension or
dry powder, without causing inflammation (Liu etal. 2018).
Physiological solid lipids, which are solid at body and room
temperatures, have a major contribution to the formation
of SLNs. These lipids are stable in surfactant-incorporated
water, which aid in blending the aqueous phase (external)
with internal lipid phase and preventing particle accumula-
tion (Weber etal. 2014). Scalable nanocarriers with a large
surface area and tiny particle size are known as SLNs. By
optimizing absorption as well as retention (EPR) based on
aberrations in tumor cell behavior including extreme vas-
cularization and inadequate lymph drainage, small particle
size of SLNs enables passive targeting, which is critical for
improving drug localization at the site of action (Shen etal.
2015). Additionally, the surface of SLNs might be easily
customized and embellished by A.O. Elzoghby etal. (2017)
(Elzoghby etal. 2017). Additionally, utilizing the proper
targeting moiety, which encourages the receptor-mediated
endocytosis of nanocarrier toward tumor cells via active tar-
geting based on fusion with receptors overexpressed in the
cell surface, the surface of SLNs might be easily tweaked
and embellished (Toloza etal. 2006). In addition to pro-
teins and nucleic acids, the solid-lipid nanostructure has
the capacity to incorporate both lipophilic and hydrophilic

Naunyn-Schmiedeberg's Archives of Pharmacology
1 3
drugs. The entrapment efficiency depends on a number of
factors, including the drug’s solubility in lipid, polymor-
phous state of lipid, lipid-matrix physico-chemical structure,
and its miscibility with lipid (Gaber etal. 2017). SLNs are
considered a good option for lipophilic drugs for improv-
ing the aqueous solubility and bioavailability and ultimately
maximize the therapeutic efficacy like chemotherapeutic
agents as etoposide, doxorubicin, and paclitaxel. Decoration
of targeting ligands on the surface of SLNs by using PEG is
also a facile approach preferentially accumulation at the site
of action (Yu etal. 2010; Sahu etal. 2015). PEGylation, on
the other hand, consequently increases the ability of SLNs
to penetrate and accumulate at the tumor site. Cationic SLNs
are one of the types that may be considered for enhancing
tumor permeability and enhancing therapeutic effectiveness
(Elzoghby etal. 2016). In comparison to bigger particles,
SLNs offer superior internalization and higher transfec-
tion because of their smaller particle size (below 100nm).
Additionally, negatively charged DNA interacts electrostati-
cally with positively charged SLNs to form lipoplex, which
enhances cellular uptake. In several lung cancer cell lines,
the wildtype p53 gene plays a critical role in tumor sup-
pression (Choi etal. 2008). Unfortunately, p53 mutations
are linked to more than 50% of NSCLCs. In order to defeat
lung cancer, it is essential to reintroduce or overexpress the
p53 gene in mutant cells. Adenovirus vectors that express
p53 were successfully transduced into NSCLC patients by
Roth etal. Phase I/II of a clinical trial saw the introduc-
tion of this tactic with success. These results corroborated
other studies that demonstrated the efficacy and safety of
transfecting p53 genes to inhibit the spread of cancer (Choi
etal. 2008). Utilizing the melt homogenization approach, a
brand-new, stable cationic SLN formulation was created to
effectively transport p53 to NSCLC mutant cells. Tricaprin
(TC) was the core forming lipid bilayer in this study, with
cationic lipid “3b [N-(N0, N0-dimethylaminoethane)carba-
moyl] cholesterol (DC-chol),” helper lipid “dioleoylphos-
phatidylethanolamine (DOPE),” and surfactant “Tween-80”
being used. Overexpression of typical oncogenes such as
“signal transducer and activator of transcription-3” which
operate as apoptosis inhibitors caused multidrug-resistance
(MDR) STAT3. Overexpression of STAT3 in NSCLC was
a sign of poor prognosis. To inhibit the STAT3 and enhance
the effect of anticancer drugs, numerous strategies are used,
such as use of chemotherapeutic moiety, STAT3 inhibitors,
and siRNA (small interfering RNAs). MDR can be defeated
by STAT3 suppression at the mRNA level (RNA interfer-
ence, RNAi) (Kotmakçı etal. 2017). However, since nucleic
acids are susceptible to nuclease enzyme breakdown, direct
administration of nucleic acids is not practical. A cationic
SLN loaded with “plasmid encoding antiSTAT3-short
hairpin RNA (STAT3-shRNA)” was synthesized. MicroR-
NAs (miRNAs) are small (18e24 nucleotide) endogenous
noncoding RNAs that operate post-transcriptionally. As
an oncogene, microRNA21 (miR-21) is a well-known
miRNA that has been linked to tumor metastasis in lung
cancer. When overexpressed, miR-21 inhibits apoptosis
and promotes proliferation. The “anti-miRNA oligonucleo-
tide (AMO)” has enormous potential for preventing cancer
(Shi etal. 2012). One promising method for overcoming
MDR and improving therapeutic outcomes in lung cancer
patients is to combine chemotherapy and gene (nucleic acid)
delivery. Targeting drugs directly to the lungs, whether for
localized or systemic treatment, is now possible thanks to
pulmonary drug delivery (Elzoghby etal. 2015). Effective
pharmacokinetic features, capability of solute exchange,
high bioavailability, thin alveolar epithelium, large surface
area, and a strong inclination to avoid the first-pass effect are
all the facts of this strategy based on the special character-
istics of lungs (Uchenna Agu etal. 2001). The biocompat-
ible lipids that are extremely well tolerated by the body and
lungs form the foundation of the SLNs safety profile. Pro-
teins and nucleic acids can be included into SLNs together
with hydrophilic and lipophilic medicines, opening up new
possibilities for medication and gene delivery.
Dendrimers
Dendrimers are polymeric nanoparticles that were initially
discovered at the end of the 1970s (Tomalia and Fréchet
2002). Dendrimers are synthesized nano-constructions
having three-dimensional architectures that are repeatedly
branched and radially symmetrical. The surface of the den-
drimers is made up of terminal chemical structures that
are covalently bonded to a core of highly repetitive units
(Sandoval-Yañez and Castro Rodriguez 2020). Dendrimers
are adaptable polymers because of their known molecular
weight, nanoscale, and monodisperse nature, as well as their
aptitude for encapsulating both hydrophilic and hydrophobic
chemotherapeutic drugs (Parajapati etal. 2016). Addition-
ally, their multipurpose surface makes surface modification
for targeted distribution simple. Such a smart drug delivery
system has the potential to release the drug at a specified
site after coming into contact with specific enzymes with
the outer functional groups, the medication can also be
delivered in a regulated manner in which mAbs and RGD
peptide like targeting molecules are employed, and including
Doxorubicin (DOX) and paclitaxel (PTX) like hydropho-
bic medications is commonly used (Hu and Zhang 2012;
Mattheolabakis etal. 2012; Lim and Simanek 2012). Drug
delivery can also be accomplished using dendrimers that
self-assembled into micelles, such as poly(glutamic acid)-
b-poly(phenylalanine) copolymers (Webster etal. 2013).
Amphiphilic diblock copolymers forming micelles are being
used in numerous clinical trials to deliver paclitaxel for the
treatment of advanced pancreatic cancer, non-small cell lung

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1 3
cancer, and breast cancer. Human breast adenocarcinoma
(MCF-7), colorectal adenocarcinoma (HT-29), non-small-
cell lung carcinoma (NCI-H460), and glioblastoma (SF-268)
were utilized to investigate the antitumor proficiency of the
dendrimer loaded with camptothecin (Morgan etal. 2006).
A study demonstrated the usage of dendrimer-targeting pep-
tide conjugates for NSCLC (Liu etal. 2011). These den-
drimer-peptide conjugates were successfully absorbed by the
tumor cells when administered to a mouse model with a lung
tumor, suggesting their promise as a therapeutic vehicle for
the targeting and management of tumor. In a separate inves-
tigation, a newly developed “PEGylated dendrimer nanopar-
ticle” showed potential as DDS based on aerosol mechanism
(Ryan etal. 2013). While larger dendrimer particles are said
to be trapped in the lung for a long time, smaller dendrimer
particles are said to enter the bloodstream through inhala-
tion. In the future, injectable medication delivery methods
could be replaced by this approach of controlled release drug
delivery system (CRDDS) to the lungs.
Metal‑based nanoparticle
As drug delivery techniques in the treatment of NSCLC, var-
ious kinds of metal-based nanoparticles, including quantum
dot, carbon nanoparticles, gold, and silver nanostructures,
have been studied. The acceptable biocompatibility of metal-
based nanoparticles and their simplicity in size and surface
modification are the main causes of the exponential expan-
sion in this field of research. They are useful for intracellu-
lar tracking due to their visible light extinction capabilities
(Oerlemans etal. 2012). Due to its greater ability to load
drugs due to pi-pi stacking between graphene sheets, in gra-
phene, a monolayer made up of carbon atoms organized in
the form of a honeycomb-like hexagonal lattice structure is
now receiving a lot of attention (SreeHarsha etal. 2019). To
make the most of graphene’s use in drug delivery systems, a
thorough understanding of its physico-chemical properties
is still lacking (Yang etal. 2019b). A thorough analysis of
the use of graphene as a versatile platform for the delivery
of drug molecules was presented by Hoseini-Ghahfarokhi
etal (Hoseini-Ghahfarokhi etal. 2020).
Strategy and research investigation of metallic nanocar-
rier, such as silver and gold, aimed toward biomedical and
biopharmaceutical characteristics have advanced signifi-
cantly in recent years. The noble metal gold nanoparticles
stand out among these because of their surface-plasmon
resonance-enhanced optical capabilities, which have been
used recently in biomedical applications with a focus on the
detection and treatment of cancer, particularly lung cancer
(Huang etal. 2007). Gold nanoparticles have recently been
tried with success as sensing agent/diagnostics for iden-
tifying and categorizing pathophysiology of various lung
cancers. The sensor could differentiate between malignant
and healthy cells, SCLC and NSCLC, and two subtypes of
LCs (Barash etal. 2012). In a study on Lewis lung cancer
animal model, methotrexate (MTX) linked gold nanopar-
ticle, a medication with excellent hydrophilic nature and
minimal tumor retention, demonstrated substantial tumor
retention and improved therapeutic efficacy (Chen etal.
2007). Numerous studies have been conducted on magnetic
nanoparticles, and they have been used in the detection and
therapy of numerous malignancies. The delivery of thera-
peutic drugs and imaging are both made easier by thera-
nostic nanoparticles. A noninvasive treatment method for
lung cancer called magnetic hyperthermia involves the heat-
induced ablation of desired tumor tissue. Superparamagnetic
iron oxide (SPIO) nanoparticles, for example, are magnetic
materials that, when exposed to alternating currents, pro-
duce sublethal heat that damages local tissue. One study
used a mouse model of NSCLC and found that the tumor-
targeted SPIO nanoparticles were very effective at inhibiting
tumor development and destroying tumors through hyper-
thermia (Sadhukha etal. 2013a). Because of their variable
drug encapsulation potential, controlled release of drugs
characteristic, and versatility, “mesoporous silica nanopar-
ticles (MSNs)” have become more frequently utilized as a
novel carrier for the delivery of chemotherapeutic agents.
Mesoporous silica nanoparticles (MSNs) were the subject of
the first study on their viability invivo, which was released
by the Mou group in 2008 (Wu etal. 2008). For animal mag-
netic resonance imaging studies and intracellular labelling,
multifunctional mesoporous silica nanoparticles have been
employed. MSNs are largely internalized by human lung
cancer cells via endocytosis (Sun etal. 2008). The devel-
opment of a cancer-targeted mesoporous silica nanoparti-
cle–associated DDS was created for the inhalation-based
treatment of lung cancer. The technology was capable of
delivering chemotherapeutic medications (cisplatin and dox-
orubicin) combined with two categories of siRNA tailored to
“MRP1 and BCL2 mRNA” in order to successfully reduce
pump and non-pump cellular resistance in NSLC (Taratula
etal. 2011). Mesoporous silica nanoparticles were capable
of targeting tumor cells because of “LHRH peptide” being
conjugated to its surface employing a poly(ethylene glycol)
(PEG) as linker.
Silver nanoparticles
Fluorescence imaging, biosensors, anticancer applications,
and other biological uses of silver nanoparticles have all
been around for a while (Mukherjee etal. 2014). He etal.
recently showed that biosynthesized silver nanoparticles
(AgNPs) have anticancer potential (He etal. 2016). By using
the trypan blue and MTT assays, the AgNPs showed a pow-
erful cytotoxic effect. Mechanistic investigations revealed
that AgNPs led to apoptosis in lung cancer cells. AgNPs’

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1 3
cytotoxicity is substantially influenced by their morphology,
surface chemistry, size, and shape (Stoehr etal. 2011). Jeong
and his group of researchers investigated the fundamental
phenomenon of hypoxia on silver nanoparticle–induced
apoptosis and found that HIF-1 expression was upregulated
in both normoxic and hypoxic circumstances. Additionally,
whereas normal cells did not experience programmed cell
death from the AgNP treatment, lung cancer cells did. Sig-
nificantly, HIF-1 prevented the AgNP-induced apoptotic
phenomenon by regulating the autophagosome flux via the
LC3-II, p62, and ATG5. The results of the research suggest
that HIF-1 could be a potential candidate for lung cancer
treatment by using hypoxia-mediated autophagy to prevent
AgNP-mediated apoptosis (Jeong etal. 2016).
Iron oxide nanoparticles
In addition to their widespread usage as MRI contrast agents,
super-magnetic iron oxide nanocarriers may be employed as
a delivery mechanism in cancer theranostics applications.
Iron oxide nanoparticles have a wide range of medical appli-
cations, including long-standing usage in cancer theranos-
tics MRI imaging, magnetic hyperthermia, and medication
delivery, in lung cancer (Noh etal. 2009). Wang etal. (2017)
have published a study on iron oxide nanoparticle–based
targeted ultrasonic ablation therapy for lung cancer (Wang
etal. 2017). In a different work, inhalable Fe2O3NPs that are
targeted at the EGFR have been shown by Sadhuka etal. to
cause hyperthermia associated with magnetic field in lung
cancer (Sadhukha etal. 2013b). The researchers demon-
strated that EGFR targeting improved iron oxide nanopar-
ticles’ tumor retention. Additionally, EGFR-targeted iron
oxide, a nanoparticle, was demonstrated in invivo magnetic
hyperthermia treatment in invivo orthotopic lung cancer
models by resulting in significant suppression of growth in
lung cancer.
Other metal nanoparticles
For theranostics applications in lung cancer, silica, nano-
diamond, and rare earth were utilized, among other nano-
particles (Sadhukha etal. 2013b). Invitro and invivo lung
cancer imaging using near-infrared tumor targeting and
p53 gene therapy was demonstrated by Wu etal. (2015)
using a silica-polymer nanocomposite (Wu etal. 2015).
When treating lung cancer, paclitaxel was also delivered
via a nano-diamond (ND). In a lung cancer cell model,
this nanodrug delivery significantly reduced tumor size in
immunodeficient animals. According to mechanistic inves-
tigations, ND triggered mitotic arrest and apoptosis, which
killed lung cancer cells. In a different experiment, Chen etal.
showed that Nd2O3 nanoparticles at micromolar concentra-
tions can significantly vacuolate NSCLC cells and trigger
a lot of autophagy (Chen etal. 2005). In order to deliver
several siRNAs (EGFR and cyclin B1) to lung cancer cells
and for bioimaging, Wu etal. (2016) synthesized quantum
dot–based carbon nanomaterial with multifunctional moiety
attachment on the surface for the establishment of a poten-
tial nano-agent (Wu etal. 2016). When activated at 360nm,
this agent creates a visible blue photoluminescence that may
be used for bioimaging. Additionally, it was found that this
nanodrug preferentially aggregated in cells of lung cancer
via endocytosis mediated by the receptor, elevating silencing
of gene as well as its anticancer efficacy.
Carbon nanotubes
Despite numerous attempts by professional teams treating
lung cancer, a lot of people continue to pass away every
year as a result of this. The prevalence of lung cancer is
widely acknowledged as being among the most pervasive
malignancies on a global level. Nanotherapy is a novel
therapeutic approach that is currently under investigation
by experts for the management of non-small cell lung cancer
(NSCLC). The disease can be effectively treated by carbon
nanotubes (CNTs) themselves by activating the apoptotic
pathway by concentrating on the organelle of mitochondria
in cancer cells. Accordingly, CNTs coupled to polyethylene
glycol may be able to target cancer cell repertoires more
effectively, thereby enhancing the effectiveness of nanodrug
delivery (Kim etal. 2017). In addition to graphene oxide,
the anticancer medication paclitaxel also formed bonds with
SWCNTs. This nanostructure improved the efficiency and
caused the death of cancer cells A549 and NCI-H460 (Arya
etal. 2013). SWCNT modified with chitosan was the subject
of a different investigation to deliver this medication and
increase invivo compatibility. Hyaluronic acid has also been
added to the layer of chitosan to specifically target A549
cells (Yu etal. 2016). Because of the enhanced distribution
along with the magnetic localization, doxorubicin delivery
by SWCNTs can improve targeting and boost therapeutic
effectiveness. The results of boosting the effectiveness of
therapy by using MRI technology were in fact validated by
this experiment, which was carried out on mice (Al Faraj
etal. 2016). In a 2018 study, curcumin was examined in a
nano-state using a SWCNT carrier, a substance created with
therapeutic promise for A549 cancer cells. The drug’s effec-
tiveness was improved by the carrier, which worked with
the polysaccharides in chitosan and alginate(Singh etal.
2018). Gemcitabine is one anticancer drug for non-small
cell lung cancer. The medication was evaluated employing
a SWCNT carrier in a clinical experiment on B6 mice. The
A549 cell line, which displays intriguing suppression results,
was the subject of this investigation. Because of the sub-
stantial loading propensity of the medicine, the extended
time of distribution, and the remarkable permeability of the

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cell membrane, this study has clearly validated SWCNTs as
stimulating carriers for the administration of medications
(Razzazan etal. 2016). To reduce drug waste and use it in
the intended manner, methotrexate may be conjugated with
MWCNTs for the treatment of lung cancer. Animal experi-
ments also showed that this compound had no negative
effects on the heart, liver, or kidneys (Das etal. 2013). The
anticancer activity of the betulinic acid–loaded MWCNTs
with acid functionality can be measured using thermogravi-
metric and UV light. Actually, certain medication concen-
trations made lung cancer cells more susceptible (Tan etal.
2014).
Biological system–based nanoparticles
forlung cancer theranostics
The incorporation of a bio-mimicking constituent into
medicinal nanostructures emerged as the primary topic of
recent investigation. This is because of the excellent biodeg-
radability, stability, and biocompatibility of bio-based nano-
particles, which include apoferritin, aptamers, viral-based
nanoparticles, SLNs, polymeric nanoparticles, and protein
nanoparticles (Sivarajakumar etal. 2018). These kinds of
nanoparticles have been successfully created, manufactured,
and applied for cancer theranostics purposes in NSCLC
(Rizvi etal. 2008).
Viral nanoparticles
Investigators are intrigued by viral nanoparticles (VNPs)
produced by viruses or bacteriophages for a variety of bio-
logical functions, such as drug delivery, biomedical imag-
ing, biosensing, and vaccine production. This is attributable
to the viral nanomaterials’ biocompatibility, adaptability in
shapes and sizes, and convenience of surface alteration (Li
etal. 2020a). In an effort to combat the challenges posed by
drug tolerance, a number of investigators have developed a
therapeutic strategy for lung cancer that combines chemo-
therapy and immunotherapy.
Protein‑based nanoparticles
Due to their exceptional biomedical applications, lack of
inflammatory response in human pulmonary cell lines,
and enhanced cellular uptake, protein nanomaterials hav-
ing natural polypeptides like legumin, gliadin, albumin,
and gelatin have been recently utilized in the delivery of
therapeutic agents whether alone or in combination form
with biodegradable polymers in the management of lung
cancer (Lohcharoenkal etal. 2014). Employing “cationic
bovine serum albumin (CBSA),” siRNA has been admin-
istered for the management of metastatic lung cancer (Han
etal. 2014b).
Apoferritin
Apoferritin is a “ferritin-based multifunctional nanocar-
rier” utilized to demonstrate the detection of lung cancer
in A549 cells by utilizing both fluorescence and MR imag-
ing (Dostalova etal. 2017; Li etal. 2012). This multipur-
pose apoferritin was employed to image cancer cells with
increased αvβ3 integrin. Another study done by Luo and
his researcher group showed the utilization of daunomycin
encapsulated apoferritin nanocages coupled to hyaluronic
acid (HA) employed for intracellular distribution and libera-
tion of anticancer drug daunomycin based on a pH-respon-
sive system (Luo etal. 2015).
Treatment anddiagnosis oflung cancer:
stimuli‑responsive drug delivery systems
Light‑responsive nanocarriers
Light has indeed frequently been utilized for remote drug
regulation because of its generally high level of safety and
non-intrusive nature (Li etal. 2020b). For on-demand medi-
cation release, photolabile groups can be directly destroyed
by short-wavelength light, like visible light or UV. Their
inability to penetrate deeply, however, limits their poten-
tial for use in biomedicine. Since near-infrared (NIR) light
(780–2500nm) may permeate the tissues more deeply
than short-wavelength light, it is necessary for the release
of medication in a controlled manner inside the biological
system. When activated by light, some nanoparticles can
significantly enhance local temperatures or activate/stimu-
late “reactive oxygen species (ROS),” which might be used
to treat malignancies. In addition, external light sources also
cause the therapeutic system’s structural changes and the
quick dissolution of photolabile groups (Ko etal. 2019).
These two methods of therapy are referred to as photother-
mal therapy (PTT) and photodynamic therapy (PDT). For
particular, employing oxygen-boosted immunogenic PDT,
researchers created core–shell gold nanocage@manganese
dioxide (AuNC@MnO2) nanoparticles to concurrently
eradicate intrinsic triple-negative breast cancer and thereby
preventing metastasis of the lung (Liang etal. 2018) and to
enhance the antitumor effectiveness while reducing adverse
effects by combining various therapeutic modalities (such
as PTT, PDT, immunotherapy, and chemotherapy). In the
interim, the ROS as well as the heat effects produced by
PTT or PDT may possibly cause the drug to be released.
Drug release induced by light can potentially be paired with

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other stimuli, such as pH, enzyme, and glutathione on the
inside and other external stimuli (like radio frequency) on
the outside, for improved targeted therapy for lung cancer
(Li etal. 2021; Gou etal. 2020; Liu etal. 2019; Pan etal.
2019). Light-responsive therapies, as previously mentioned,
have a variety of advantages and show tremendous promise
for the therapeutic treatment of lung cancer. Furthermore,
during the course of the treatment, light-absorbing mole-
cules that produce temperature or increase “ROS” can emit
fluorescence or convert the temperature into something like
a photoacoustic (PA) signal. These compounds are used in
imaging diagnosis.181
pH‑responsive nanocarriers
Tumor cells have a significantly more acidic environment
(pH 5.7–6.9) due to the presence of lactic acid and perhaps
by some end products formed by lung carcinoma cells that
is linked to an unusual accelerated metabolism as well as
the proliferation in contrast to normal physiological tissues
(Kanamala etal. 2016). Besides increasing the accrual of
nanocarrier in tumor cells and strengthening the consist-
ency and protection of therapeutic strategies for the treat-
ment of lung cancer, the release of drug/chemotherapeutics
can be controlled inside the tumor microenvironment or even
can minimize the drug release to the tumor by employing
pH-sensitive nanoparticles. Lee and team discovered that
an acidic pH could effectively activate cholesteryl hemisuc-
cinate (CHEMS)–based liposomes, indicating that pH-sensi-
tive nanostructures loaded with anticancer drugs have excep-
tional anticancer activity against NSCLC. The poor outlook
of NSCLC patients was attributed to the folate receptor beta
(FR) that was commonly highly expressed in M2 tumor-
associated macrophages (TAMs) as well as NSCLC cells
(Park etal. 2021). To make pH-sensitive liposomes for reg-
ulated drug release, CHEMS (which is unstable in acidic
conditions) was coupled to PEG-folate. A mixed micellar
system including poly-benzyl-glutamate and d-tocopherol
polyethylene glycol succinate may be able to modify the sec-
ondary poly-benzyl-glutamate complexes by regulating the
release of DOX. The DOX encapsulated conjugated/mixed
micelles showed exceptional therapeutic effects against lung
cancer when used on naked mice injected with human lung
cancer A549 cells (Shih etal. 2020). For the management of
lung carcinoma, the acidic pH of the tumor microenviron-
ment could also cause charge reversal to encourage intracel-
lular uptake and nuclear translocation. Despite indiscrimi-
nate adsorption, nanocomposites having positive exterior
potential often have shorter circulation of blood half-lives.
This issue was rectified by using TAT peptide by increasing
tumor cells’ absorption of the drug. Anhydride (DA) groups
can hide TAT’s positive charges. After the aggregation of
carriers in the tumor’s acidic medium, the charge was flipped
from negative to positive, restoring TAT’s targeting poten-
tial. To combat lung tumors, Jing etal. created a “DA-TAT”
vehicle for pH-responsive nuclear targeting and cellular
uptake (Jing etal. 2018). Shi etal. constructed pH-triggered
nanocomposite utilizing a tri-block copolymer consisting of
“poly(sulfadimethoxine), methoxy poly (ethylene glycol)-
poly(histidine), and poly(histidine) as mPEG-PHis-PSD.”
PSD’s charge was immediately changed from negative to
neutral by an acidic pH, which caused it to quickly dissoci-
ate from the lipid core. This made it possible for NSCLC
medication to effectively internalize, accumulate specifically
in tumors, and have an anticancer effect (Shi etal. 2018).
Enzyme‑responsive nanocarriers
In order to sustain an organism’s regular processes, such
as development, growth, disease, metabolism, immunity,
and aging, enzymes are crucial biomolecules. Abnormal
enzymatic expression was commonly observed in several
illnesses’ cellular microenvironments, particularly in lung
cancer (Chen etal. 2018; Sharma etal. 2018). Hyaluroni-
dase (HAase), matrix metalloproteinases (MMPs), esterase,
quinone oxidoreductase, and NADPH are the most com-
monly overexpressed enzymes (NQO1). Due to the selectiv-
ity, efficacy, and speed of enzymatic responses in treating
lung cancer, enzyme-responsive nanoparticles have received
a lot of interest (Shahriari etal. 2019; Wang etal. 2018).
For instance, the MMP family of proteolytic zinc-dependent
secreted endopeptidases may precisely break down a range of
extracellular matrix components (ECMs). The introduction
of drug delivery based on enzyme-responsive devices may
take advantage of abnormally high MMP expression in lung
carcinoma tissues (Egeblad and Werb 2002). For targeted
lung cancer therapy, MMP-responsive peptides or gelatin is
typically adhered to the surfaces of nanoparticles (Fan etal.
2017). This is predicated on the notion that collagen as well
as basement membrane can be preferentially broken down
by MMP-2 and MMP-9. Gianneschi constructed an MMP-
9-associated nanostructure for the purpose of delivering the
“immunotherapeutic small molecule (1V209)” for stimula-
tion of the immune system. The previously stated platform
improved medication efflux and prevented lung tumor spread
invivo (Li etal. 2019). Additionally, gelatin can act as the
carrier skeleton and serve as a substrate for MMPs. As the
extensive treatment approach of lung tumors, the complexed
gelatin and cisplatin create an intelligent inhalable nanocar-
rier. When subjected to physiological solutions, cisplatin was
swapped with chloride ions after gelatin was broken down,
which caused the drug to be quickly released at the tumor
location (Vaghasiya etal. 2021). To enhance the efficiency
of treatment for lung cancer, HAase is typically coupled with
multi-responsive nanoparticles. The hydrophilic shell was
built using hyaluronic acid (HA), and hydrophobic chemicals

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could be added to the HA structure via a conjugation mecha-
nism. In contrast, by employing pH-sensitive hydrazone cou-
plings, Tang and coworkers developed hyaluronic acid (HA)
NPs that are both pH and enzymatic responsive (Ren etal.
2019). He and colleagues created HPGBCA nanostructure
for the delivery of “afatinib” via carrier-mediated targeting
mechanism for the management of NSCLC therapy. Another
excellent option is an esterase-sensitive nanocarrier which
has been employed to deliver chemotherapeutics toward lung
cancer cells based on enzyme-responsive phenomena. For
the treatment of lung cancer, Cho and colleagues created the
HAPBA nanoparticle, which would release medications in an
esterase-rich environment within the tumor tissue. HA was
conjugated 4-phenylbutyric acid (PBA) via ester linkage to
regulate and control the rapid liberation of PBA-curcumin.
PBA served as both the hydrophobic section and an effective
histone deacetylase inhibitor in the formation of these nano-
particles (HDAC). When ester bonds were broken, curcumin
and PBA were released quickly, effectively slowing down
the growth of lung adenocarcinomas (Lee etal. 2019). A
curcumin-gold nanorod coupled nanostructure was created
by using an “esterase-labile ester link” demonstrated by Ren
etal. This compound displayed a curcumin release that was
both quick and consistent (Ren etal. 2019). In the absence
of esterase, the amount of loaded therapeutic agent was fully
constrained within the nanomaterials. Curcumin was released
suddenly as esterase concentration increased, indicating that
ester hydrolysis was a crucial catalyst for drug release. As
a result, the nanorod-associated curcumin-coupled nanocar-
rier inhibitory potential on human lung cancer cells (A549)
was enhanced by the introduction of the ester linkage (Zhu
etal. 2018).
Vaccine‑based therapy forNSCLC
Historically, the word “vaccine” has been associated with
the medical practice of treating infectious disorders by the
induction of humoral immunity toward infectious agents.
In the process of developing therapeutic vaccines, several
forms of vaccinations have acted as a source of motivation
(Banchereau and Palucka 2018). The former are intended
to cure a condition by enhancing the cellular and humoral
responses of the immune system, particularly those of T
cells. The discovery of mutant proteins that are undesirably
produced by cancer cells gave birth to the idea of develop-
ing a vaccination for cancers. These are recognized by the
immune function as “tumor-associated antigens (TAA),” and
they are able to be separated into two categories: expressed
fetal antigens, which are ordinarily lacking in healthy adults,
and overexpressed normal proteins (Cuppens and Vansteen-
kiste 2014; Cortés‐Jofré etal. 2019). The basic operating
concept of medicated vaccinations is that they function by
instructing the immune system to detect and react appropri-
ately to certain antigens. Numerous vaccination approaches,
such as whole-cell (Xia etal. 2016; Ward etal. 2002) pep-
tide/protein-based (Wada etal. 2017) and mRNA-associated
(Sebastian etal. 2011, 2014) vaccines have been investi-
gated as potential treatments for non-small cell lung cancer
(NSCLC) (Table1). In this essay, we will concentrate on
mRNA, peptide, and protein, peptide since there have been
some noteworthy breakthroughs surrounding the encapsula-
tion of these types of vaccines utilizing nanoparticles.
Nanoparticle‑associated ongoing clinical
trials formanagement ofNSCLC
The therapeutic effects of nanoparticles are mostly deter-
mined by their function, which is also highly determined by
their shape and materials (Shi etal. 2017b). Additionally, by
changing these properties, it is feasible to employ them as
contrast agents for CT/PET imaging methods, consequently
establishing multifunctional theranostic platforms (Li etal.
2016b). The researchers were capable of identifying possible
targets for repurposing depending on the mode of action by
employing different repurposing methodologies. Neverthe-
less, there were only a few medications that made it to the
level of clinical trials. Glucocorticoids are the most preva-
lent class of pharmaceuticals in clinical studies exploring
prospective therapies for repurposing in the management
of non-small cell lung cancer. The recent/ongoing clinical
investigation for the treatment of NSCLC based on nanopar-
ticle system is mentioned in Table2.
Conclusions andfuture perspectives
In conclusion, fresh applications for usage in cancer diagnosis,
detection, imaging, and treatment are constantly being devel-
oped, demonstrating the limitless promise of nanoparticle-
based medicine. Nanoparticles are the best delivery systems
for the treatment of lung cancer because they may be specifi-
cally designed for a personalized medicine approach. Recog-
nizing cancer physiology, tumor’s microenvironment, and
the engagement of tumor cells with nanoparticles is essential
for the future development of various techniques to specifi-
cally deliver medications to lung tumors and lung metasta-
ses. Oncologists now have a larger selection of medications
at their disposal thanks to polymer conjugates and particulate
nanocarriers. These currently rely on passive tissue targeting
rather than active cellular targeting, primarily through EPR.
Theranostics, or individualized treatment for cancer, is based
on a personalized prescription and therefore it is evidence-
based to ensure the precise administration of medicines or the
effective treatment at the correct time, improving the patient’s

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Table 1 Vaccine-associated ongoing investigation for management of NSCLC
Vaccine system Title of clinical trial Clinical
trial phase
NSCLC-stage ClinicalTrials.
gov identifier
References
DNA vaccine “NY-ESO-1 plasmid DNA (pPJV7611)” I–II III–IV NCT00199849 ClinicalTrials.gov
Identifier:NCT00199849
(2005)
“Plasmid encoding neoepitopes (VB10.
NEO) and Bempegaldesleukin (NKTR-
214)”
I–II III–IV NCT03548467 ClinicalTrials.gov
Identifier:NCT03548467
(2018)
mRNA vaccine “Autogene Cevumeran (RO7198457) as a
Single Agent and in Combination With
Atezolizumab”
I II–IV NCT03289962 ClinicalTrials.gov
Identifier:NCT03289962
(2017)
“mRNA-5671/V941 as Monotherapy and
in Combination With Pembrolizumab
(V941-001)”
I III–IV NCT03948763 ClinicalTrials.gov
Identifier:NCT03948763
(2019)
“messenger ribonucleic acid (mRNA)
Vaccine [BI 1361849] + anti-pro-
grammed death ligand 1 (PD-L1) [dur-
valumab] + anti-cytotoxic T-lympho-
cyte-associated protein 4 (CTLA-4)
antibody”
I–II III–IV NCT03164772 ClinicalTrials.gov
Identifier:NCT03164772
(2017)
Peptide vaccine “Phase III Trial of OSE2101 as 2nd or
3rd Line Compared With Standard
Treatment (Docetaxel or Pemetrexed)
in HLA-A2 Positive Patients”
III III–IV NCT02654587 ClinicalTrials.gov
Identifier:NCT02654587
(2016)
“Therapeutic Vaccination Using
Telomerase-derives Universal Cancer
Peptides in Metastatic Non Small Cell
Lung Cancer”
I–II III NCT02818426 ClinicalTrials.gov
Identifier:NCT02818426
(2016)
“EMD531444(L-BLP25 or BLP25 Lipo-
some Vaccine)”
I-II III NCT00960115 ClinicalTrials.gov
Identifier:NCT00960115
(2009)
“UV1 Vaccination (UV1-hTERT2012L)” I–II III NCT01789099 ClinicalTrials.gov
Identifier:NCT01789099
(2013)
“IDO peptide with With Immune Stimu-
lating Agent Aldara and the Adjuvant
Montanide”
I III–IV NCT01219348 ClinicalTrials.gov
Identifier:NCT01219348
(2010)
Protein vaccine “Recombinant PRAME protein com-
bined with the AS15 Adjuvant System
GSK2302032A”
II I–IIIA NCT01853878 ClinicalTrials.gov
Identifier:NCT01853878
(2013)
“Tumor Antigen-loaded Dendritic Cell-
derived Exosomes (CSET 1437)”
II III–IV NCT01159288 ClinicalTrials.gov
Identifier:NCT01159288
(2010)
“Vaccine gp96-Ig Fusion Protein
(Ad100-gp96Ig-HLA A1)”
I III–IV NCT00503568 ClinicalTrials.gov
Identifier:NCT00503568
(2007)
“MUC1 Peptide—Poly-ICLC (Polyi-
nosinic-polycytidylic Acid Stabilized
With Polylysine and Carboxymethyl-
cellulose) OR HILTONOL™ Adjuvant
Vaccine”
I–II III NCT01720836 ClinicalTrials.gov
Identifier:NCT01720836
(2012)

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condition and lowering the cost of drugs and services. Using a
delivery platform based on nanotechnology, theranostics med-
icine is used to deliver imaging and therapeutic substances to
the predetermined specific location via site-specific target-
ing (i.e., lung cancer cell). Nanomaterials have shown to be
extremely useful tools and are now being used in medical set-
tings. Due to their new physical characteristics, nanostructures
can frequently resolve problems with solubility as well as sta-
bilization via interface modifications or supplementary prepa-
rations. Targeted drug delivery and diagnostics nanostructures
are made possible by the assimilated method of integrating
biomacromolecules, carriers, medications, and diagnostic
material. The nanometric size range molecules have larger
surface area which contributes to the higher therapeutic pay-
load as well. Targeting specific cancer cells with nanoparticles
and delivering therapeutic payloads to cancer areas with preci-
sion through “active and passive targeting” can greatly lower
nonspecific cytotoxicity. Despite the benefits, there are still
many obstacles that need to be resolved, like cost-effective
manufacturing, scale-up concerns, imaging approach, and the
pharmacokinetics of drugs. To see lung cancer theranostics
reach the clinic, more concerns with nanotoxicity and regu-
latory rules and barriers need to be tackled. Although nano-
technology has made significant progress, it is still not being
utilized to its full potential in lung and other cancers. Stronger
sequencing, immunohistochemistry, and proteomic techniques
are now available, which will lead to a greater understand-
ing of the mechanisms behind cancer as well as the discov-
ery of novel, conclusive biomarkers. The development of
key genomic programs like the “human protein atlas, cancer
Table 1 (continued)
Vaccine system Title of clinical trial Clinical
trial phase
NSCLC-stage ClinicalTrials.
gov identifier
References
Cellular vaccine “DCVAC/LuCa Added to Standard
First Line ChT With Carboplatin
and Paclitaxel ± Immune Enhancers
(Interferon-α and Hydroxychloro-
quine)” (Allostim®)
I–II IV NCT02470468 ClinicalTrials.gov
Identifier:NCT02470468
(2015)
“Autologous dendritic cells pulsed with
allogenic tumor cells” (MelCancer-
Vac®)
II III–IV NCT00442754 ClinicalTrials.gov
Identifier:NCT00442754
(2007)
“Allogenic whole tumor cells” (Lucanix
®)
III III–IV NCT00676507 ClinicalTrials.gov
Identifier:NCT00676507
(2008)
“MIDRIXNEO-LUNG, an Autologous
Neoantigen-targeted Dendritic Cell
Immunotherapy”
I III–IV NCT04078269 ClinicalTrials.gov
Identifier:NCT04078269
(2019)
“Allogeneic Cellular Vaccine 1650-G” II I–II NCT00654030 ClinicalTrials.gov
Identifier:NCT00654030
(2008)
Table 2 Nanoparticle-associated ongoing clinical trials for management of NSCLC (Doumat etal. 2023)
Nanoparticles Drug employed Condition-stage Clinical trial phase ClinicalTrials.
gov identifier
References
Liposome Lurtutecan NSCLC IIIB I NCT00006036 ClinicalTrials.gov Identifier:NCT00006036 (2004)
Camptothecin NSCLC IIIB-IV Preclinical NCT00277082 ClinicalTrials.gov Identifier:NCT00277082 (2006)
Doxorubicin NSCLC IIIB I NCT01051362 ClinicalTrials.gov Identifier:NCT01051362 (2010)
Doxorubicin NSCLC IIIB-IV II NCT00020124 ClinicalTrials.gov Identifier:NCT00020124 (2003)
Polymeric micelle Paclitaxel NSCLC IV II NCT01023347 ClinicalTrials.gov Identifier:NCT01023347 (2009)
Paclitaxel NSCLC III NCT02667743 ClinicalTrials.gov Identifier:NCT02667743 (2016)
Nanoparticles Paclitaxel NSCLC II II NCT01620190 ClinicalTrials.gov Identifier:NCT01620190 (2012)
Docetaxel NSCLC II NCT02283320 ClinicalTrials.gov Identifier:NCT02283320 (2014)
Docetaxel NSCLC II NCT01792479 ClinicalTrials.gov Identifier:NCT01792479 (2013)
Carboplatin NSCLC IIIB-IV II NCT00729612 ClinicalTrials.gov Identifier:NCT00729612 (2008)

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proteome studies, and The Cancer Genome Atlas (TCGA)”
and increased financing for multi-center cohort research all
advanced our understanding of cancer. In a single nanoscale
package, multifunctional nanocarriers provide earlier detec-
tion, diagnostic capabilities, targeted medication distribution
via several pathways, and therapy evaluation. These advan-
tages are especially significant for adenocarcinomas that have
MDR, such as NSCLC. It is crucial to explore alternatives
to traditional chemotherapeutic therapies because NSCLC
is one of the most deadly cancers, with one of the highest
fatality rates. Nowadays, nanomedicine is a vital option for
the treatment of NSCLC, and it may serve a deciding role in
the approaching transformation of a tailored comprehensive
therapy.
Author contribution Conceptualization: Sumel Ashique, Ashish Garg,
and Neeraj Mishra; methodology: Sumel Ashique, Neha Raina, Radha
Rani, and Long Chiau Ming; formal analysis and investigation: Sumel
Ashique, Neha Raina, Madhu Gupta; writing—original draft prepa-
ration: Sumel Ashique, Ashish Garg, and Neeraj Mishra; writing—
review and editing: Ashish Garg, Neeraj Mishra, and Madhu Gupta.
The authors confirm that no paper mill and artificial intelligence was
used.
Data availability This document includes citations for all the data that
were analyzed throughout the literature review.
Declarations
Ethics approval and consent to participate Not applicable.
Consent for publication All the authors have read the manuscript and
have approved this submission.
Competing interests The authors declare no competing interests.
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