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A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy Against Solid Tumors

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Advanced Materials
Authors:
Lingxiao Zhang at Aarhus University
Lingxiao Zhang
Jing Zhao
Jing Zhao
Jing Zhao
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Xi Hu at Zhejiang University
Xi Hu
Chenhan Wang
Chenhan Wang
Chenhan Wang
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Abstract and Figures

Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there is unavoidable non‐specific toxicities due to the pleiotropy of cytokines and undesired activation of off‐target cells. Herein, we report a Zn2+ doped layered double hydroxide (Zn‐LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity. Peritumorally injected Zn‐LDH sustainably neutralizes acidic TME and releases abundant Zn2+, promoting a pro‐inflammatory network composed of M1‐tumor‐associated macrophages, cytotoxic T cells and natural‐killer cells. Moreover, the Zn‐LDH internalized by tumor cells effectively disrupts endo‐/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas‐STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor‐associated antigens to induce antigen‐specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn‐LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. Our study provides a rational bottom‐up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors. This article is protected by copyright. All rights reserved
Characterization of Zn‐LDH. a,b) TEM images of LDH and Zn‐LDH. c) Zn, O, Mg, and Al element analysis in Zn‐LDH by EDS. d) XRD patterns of LDH and Zn‐LDH (* and + denote characteristic peaks of ZnO and Zn(OH)2, respectively). e) Size distribution of LDH, Zn‐LDH‐n (n denotes the ZnCl2 precursor concentration) and ZnAl‐LDH. f) pH of deionized water containing LDH, Zn‐LDH‐n, and ZnAl‐LDH (250 and 500 µg mL⁻¹). g) Maturation of DC2.4 cells treated with LDH, Zn‐LDH‐n, and ZnAl‐LDH. h) OVA adsorption isotherm on LDH and Zn‐LDH fitted in a Langmuir model. i) Expression of MHC‐I/SIINFKEL by DC2.4 after incubated with ZnCl2 + free OVA, LDH/OVA, and Zn‐LDH/OVA. j) pH of culture medium in 24‐well plate seeded with B16F10 tumor cells in the presence or absence of LDH and Zn‐LDH (500 µg mL⁻¹). k) Release profiles of Zn²⁺ from Zn‐LDH in PBS with various pH (pH 5.5, 6.5, and 7.4). l) Zn²⁺ release profiles from Zn‐LDH at various pH (pH 5.5, 6.5, and 7.4) in the transwell. Data are means ± SEM. Statistical significance is calculated by one‐way ANOVA with Tukey's post hoc test.
Characterization of Zn‐LDH. a,b) TEM images of LDH and Zn‐LDH. c) Zn, O, Mg, and Al element analysis in Zn‐LDH by EDS. d) XRD patterns of LDH and Zn‐LDH (* and + denote characteristic peaks of ZnO and Zn(OH)2, respectively). e) Size distribution of LDH, Zn‐LDH‐n (n denotes the ZnCl2 precursor concentration) and ZnAl‐LDH. f) pH of deionized water containing LDH, Zn‐LDH‐n, and ZnAl‐LDH (250 and 500 µg mL⁻¹). g) Maturation of DC2.4 cells treated with LDH, Zn‐LDH‐n, and ZnAl‐LDH. h) OVA adsorption isotherm on LDH and Zn‐LDH fitted in a Langmuir model. i) Expression of MHC‐I/SIINFKEL by DC2.4 after incubated with ZnCl2 + free OVA, LDH/OVA, and Zn‐LDH/OVA. j) pH of culture medium in 24‐well plate seeded with B16F10 tumor cells in the presence or absence of LDH and Zn‐LDH (500 µg mL⁻¹). k) Release profiles of Zn²⁺ from Zn‐LDH in PBS with various pH (pH 5.5, 6.5, and 7.4). l) Zn²⁺ release profiles from Zn‐LDH at various pH (pH 5.5, 6.5, and 7.4) in the transwell. Data are means ± SEM. Statistical significance is calculated by one‐way ANOVA with Tukey's post hoc test.
… 
Zn‐LDH induces cell apoptosis and interferes with autophagy. a) Confocal laser scanning microscopy (CLSM) images of 2,7‐dichlorofluorescein diacetate (DCFH‐DA, cellular ROS indicator) staining in B16F10 cells after incubating with indicated treatments. b) CLSM images of a 5,5′,6,6′‐tetrachloro‐1,1′,3,3′‐tetraethyl‐imidacarbocyanine (JC‐1) probe in B16F10 cells with indicated treatments. The increased JC‐1 monomer signal denotes the decrease of mitochondrial membrane potential. c) CLSM images of the colocalization of Zn‐LDH with autophagolysosomes in B16F10 cells after incubation for 4 or 24 h. d,e) Quantitative polymerase chain reaction (q‐PCR) analysis of the relative levels of LC3B (d) and P62 (e) mRNA in B16F10 cells with indicated treatments for 24 h. f) Expression of LC3‐I/II in tumor cells treated with LDH, Zn‐LDH, and chloroquine (CQ) for 24 h. The ratio of LC3‐II/I is calculated by comparing their band densities, and the ratio of LC3‐II/I in saline group is defined as 1.00. Data are means ± SEM. Statistical significance is calculated by one‐way ANOVA with Tukey's post hoc test.
Zn‐LDH induces cell apoptosis and interferes with autophagy. a) Confocal laser scanning microscopy (CLSM) images of 2,7‐dichlorofluorescein diacetate (DCFH‐DA, cellular ROS indicator) staining in B16F10 cells after incubating with indicated treatments. b) CLSM images of a 5,5′,6,6′‐tetrachloro‐1,1′,3,3′‐tetraethyl‐imidacarbocyanine (JC‐1) probe in B16F10 cells with indicated treatments. The increased JC‐1 monomer signal denotes the decrease of mitochondrial membrane potential. c) CLSM images of the colocalization of Zn‐LDH with autophagolysosomes in B16F10 cells after incubation for 4 or 24 h. d,e) Quantitative polymerase chain reaction (q‐PCR) analysis of the relative levels of LC3B (d) and P62 (e) mRNA in B16F10 cells with indicated treatments for 24 h. f) Expression of LC3‐I/II in tumor cells treated with LDH, Zn‐LDH, and chloroquine (CQ) for 24 h. The ratio of LC3‐II/I is calculated by comparing their band densities, and the ratio of LC3‐II/I in saline group is defined as 1.00. Data are means ± SEM. Statistical significance is calculated by one‐way ANOVA with Tukey's post hoc test.
… 
Zn‐LDH induces ICD. a) CLSM images of intracellular HMGB1 distribution in B16F10 tumor cells treated with ZnCl2, LDH, and Zn‐LDH. b) Quantitative analysis of the ATP release in B16F10 tumor cells treated with ZnCl2, LDH, and Zn‐LDH. c–f) q‐PCR analysis of the relative levels of CRT (c), PD‐L1 (d), CD47 (e), and P53 (f) mRNA in B16F10 cells with indicated treatments for 24 h. g,h) Phagocytosis of dying B16F10 cells by DC2.4 and Raw264.7. i) Relative mRNA levels of ISG56 and IFNB1 in B16F10 cells with indicated treatments for 24 h. j,k) Antigen presentation by DCs and macrophages in tdLNs. Data are means ± SEM. Statistical significance was calculated by one‐way ANOVA with Tukey's post hoc test.
Zn‐LDH induces ICD. a) CLSM images of intracellular HMGB1 distribution in B16F10 tumor cells treated with ZnCl2, LDH, and Zn‐LDH. b) Quantitative analysis of the ATP release in B16F10 tumor cells treated with ZnCl2, LDH, and Zn‐LDH. c–f) q‐PCR analysis of the relative levels of CRT (c), PD‐L1 (d), CD47 (e), and P53 (f) mRNA in B16F10 cells with indicated treatments for 24 h. g,h) Phagocytosis of dying B16F10 cells by DC2.4 and Raw264.7. i) Relative mRNA levels of ISG56 and IFNB1 in B16F10 cells with indicated treatments for 24 h. j,k) Antigen presentation by DCs and macrophages in tdLNs. Data are means ± SEM. Statistical significance was calculated by one‐way ANOVA with Tukey's post hoc test.
… 
Zn‐LDH modulates TME to potentiate in situ tumor metalloimmunotherapy. a) SNARF‐1 fluorescence (measured at 580 and 640 nm) images of tumors collected from mice treated with saline, LDH and Zn‐LDH for 24 h. b) Estimated pH value of tumors in (a) by calculating the I580/640 refers to the ratio of the average fluorescence density of the tumor at the wavelength of 580 and 640 nm. c–g) Levels of M2‐like TAMs, M1‐like TAMs, CD8⁺ T cells, CD4⁺ T cells, and NK cells in B16F10 tumors. h,i) Levels of mature DCs (CD11c⁺ CD80⁺ and CD11c⁺ CD86⁺) in tdLNs. j,k) Levels of antigen‐specific CD3⁺ CD8⁺ T cells (j) and CD3⁺ CD4⁺ T cells (k) in splenocytes. l) Schematic illustration of the mechanism of Zn‐LDH‐mediated TME modulation. n = 3 in all groups. Data are means ± SEM. Statistical significance is calculated by one‐way ANOVA with Tukey's post hoc test.
Zn‐LDH modulates TME to potentiate in situ tumor metalloimmunotherapy. a) SNARF‐1 fluorescence (measured at 580 and 640 nm) images of tumors collected from mice treated with saline, LDH and Zn‐LDH for 24 h. b) Estimated pH value of tumors in (a) by calculating the I580/640 refers to the ratio of the average fluorescence density of the tumor at the wavelength of 580 and 640 nm. c–g) Levels of M2‐like TAMs, M1‐like TAMs, CD8⁺ T cells, CD4⁺ T cells, and NK cells in B16F10 tumors. h,i) Levels of mature DCs (CD11c⁺ CD80⁺ and CD11c⁺ CD86⁺) in tdLNs. j,k) Levels of antigen‐specific CD3⁺ CD8⁺ T cells (j) and CD3⁺ CD4⁺ T cells (k) in splenocytes. l) Schematic illustration of the mechanism of Zn‐LDH‐mediated TME modulation. n = 3 in all groups. Data are means ± SEM. Statistical significance is calculated by one‐way ANOVA with Tukey's post hoc test.
… 
Evaluation of the antitumor efficacy of Zn‐LDH on melanoma and breast cancer mice. a) Time frame for the treatment of melanoma mice (n = 6). b,c) The average and individual volume of the primary melanoma tumor treated with saline, ZnCl2 (142 µg per mouse), LDH (1 mg per mouse), or Zn‐LDH (1 mg per mouse), respectively. d,e) The average and individual volume of the distant melanoma tumor without treatments. f) Time frame for the treatment of breast cancer mice (n = 8). g,h) The average and individual volume of the primary breast cancer tumors treated with saline, ZnCl2 (142 µg per mouse), LDH (1 mg per mouse), or Zn‐LDH (1 mg per mouse), respectively. i) H&E analysis of the lung metastasis in breast cancer mice at day 23. j) Time frame for the treatment of breast cancer mice and optical image for the surgery (n = 8). When the tumor volume reached 50 mm³, about 90% of the tumor was removed by surgery, then saline or Zn‐LDH (1 mg per mouse) was injected around the wound 1 d after surgery. k,l) The average and individual volume of the volume of tumor at the surgical site. m) H&E staining analysis of the lung metastasis of mice. Animals were euthanized when the tumor volume exceeded 1500 mm³ or the mouse was very unhealthy. Data are means ± SEM. Statistical significance is calculated by two‐way ANOVA with Tukey's post hoc test.
+1
Evaluation of the antitumor efficacy of Zn‐LDH on melanoma and breast cancer mice. a) Time frame for the treatment of melanoma mice (n = 6). b,c) The average and individual volume of the primary melanoma tumor treated with saline, ZnCl2 (142 µg per mouse), LDH (1 mg per mouse), or Zn‐LDH (1 mg per mouse), respectively. d,e) The average and individual volume of the distant melanoma tumor without treatments. f) Time frame for the treatment of breast cancer mice (n = 8). g,h) The average and individual volume of the primary breast cancer tumors treated with saline, ZnCl2 (142 µg per mouse), LDH (1 mg per mouse), or Zn‐LDH (1 mg per mouse), respectively. i) H&E analysis of the lung metastasis in breast cancer mice at day 23. j) Time frame for the treatment of breast cancer mice and optical image for the surgery (n = 8). When the tumor volume reached 50 mm³, about 90% of the tumor was removed by surgery, then saline or Zn‐LDH (1 mg per mouse) was injected around the wound 1 d after surgery. k,l) The average and individual volume of the volume of tumor at the surgical site. m) H&E staining analysis of the lung metastasis of mice. Animals were euthanized when the tumor volume exceeded 1500 mm³ or the mouse was very unhealthy. Data are means ± SEM. Statistical significance is calculated by two‐way ANOVA with Tukey's post hoc test.
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A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe
Metalloimmunotherapy Against Solid Tumors
Lingxiao Zhang, Jing Zhao, Xi Hu, Chenhan Wang, Yingbo Jia, Chaojie Zhu, Shangzhi Xie, Jiyoung Lee,
Fangyuan Li*, and Daishun Ling*
Dr. L. Zhang, J. Zhao, Dr. X. Hu, C. Wang, C. Zhu, S. Xie, J. Lee, Prof. F. Li, Prof. D. Ling
Institute of Pharmaceutics, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical
Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
E-mail: dsling@sjtu.edu.cn (D. Ling), ORCID: 0000-0002-9977-0237 (D. Ling); lfy@zju.edu.cn (F. Li)
Prof. D. Ling
Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical
Engineering, State Key Laboratory of Oncogenes and Related Genes, National Center for
Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
Dr. X. Hu
Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine,
Hangzhou 310003, P. R. China
Prof. F. Li, Prof. D. Ling
WLA Laboratories, Shanghai 201203, P. R. China
C. Wang
Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, Nanjing,
210029, P. R. China.
This article is protected by copyright. All rights reserved.
2
Y. Jia
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy
of Sciences, Beijing 100190, P. R. China.
Keywords: vaccine adjuvants, immunogenic cell death, layered double hydroxide, nutritional metal
ions, tumor microenvironment
This article is protected by copyright. All rights reserved.
3
Abstract: Clinical immunotherapy of solid tumors elicits durable responses only in a minority of
patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although
rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that
relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there is
unavoidable non-specific toxicities due to the pleiotropy of cytokines and undesired activation of off-
target cells. Herein, we report a Zn2+ doped layered double hydroxide (Zn-LDH) based
immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust
antitumor immunity. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases
abundant Zn2+, promoting a pro-inflammatory network composed of M1-tumor-associated
macrophages, cytotoxic T cells and natural-killer cells. Moreover, the Zn-LDH internalized by tumor
cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and
the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death,
which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T
lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic
inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and
metastasis of solid tumors in mice. Our study provides a rational bottom-up design of potent adjuvant
for cancer metalloimmunotherapy against solid tumors.
This article is protected by copyright. All rights reserved.
4
1. Introduction
-
    
        -

-
              

 -      -   
          -   

         
   -         -
-
          -
        
          -
-    -      

           
     
 -
   --  -    

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            
             
              
            
      -    


  --      
          
    Scheme 1 -   
-

         

  --

around the peripheral of the tumorpenetrate
into the deep tissues -  -        
-
  -       -  
          -
-
      -  -    
together with the phagocytosis of dying tumor cells by dendritic cells (DCs) and macrophages in the
, thus enhancing antigen presentation- 
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6

          
 -

Scheme 1.           
-

   -  -
 -
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7

        

    -        
-together with the
phagocytosis of dying tumor cells by DCs and macrophages in the TME, thus enhancing antigen
presentation   -        

2. Results and Discussion
2.1. Synthesis and Characterization of Zn-LDH

Figure 1     -     
              
-
--
             
 --
             

--
              - 
           
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     -  

-----


        -  -    - 

-
-
- --  --        
 --   -        
           The antigen-presenting
capacities of LDH and Zn-LDH were further detected using ovalbumin (OVA) as a model antigen.
Firstly, LDH and Zn-LDH with positive charges (Figure S2b, Supporting Information) and large surfaces
exhibit outstanding protein adsorption capacities (Figure 1h). Moreover, the T cell epitope of OVA
(SIINFKEL) presented by DCs in Zn-LDH group is notably higher than that of Zn2+ + OVA or LDH group
(Figure 1i; Figure S4, Supporting Information), owing to both Zn2+ doping and the great antigen-
presenting capacity of Zn-LDH. These results indicate that the introduction of Zn2+ effectively
elevates the adjuvanticity of Zn-LDH to promote DCs maturation and antigen presentation.
  
---


--

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
-      
Besides, the size of Zn-LDH keeps relatively stable
in pH 7.4 PBS (Figure S5, Supporting Information).-
-


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Figure 1. ---
     -        -   
--nn
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-
--n--
--n- OVA adsorption isotherm on LDH and Zn-LDH fitted in a Langmuir
model. (i) The expression of MHC-I/SIINFKEL by DC2.4 after incubated with ZnCl2 + free OVA,
LDH/OVA and Zn-LDH/OVA.-
 -  - 
--
  Data are means ± SEM.
-
2.2. Zn-LDH Interferes with Autophagy and Induces ICD
   -         - - 
-
--
 

-  Figure 2
         


 -
--
            
 
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--
 Excitingly, we found that Zn-LDH efficiently increases the expression of phagophore-
incorporated autophagy markers, such as LC3-II and P62 in tumor cells (Figure 2e,f; Figures S9 and
S10, Supporting Information), which are normally over-expressed upon the treatment of autophagy-
inhibition drugs (e.g., chloroquine diphosphate (CQ)).[26]acridine orange (AO) was utilized
to detect the integrity of the lysosomal membrane.[12b] Zn-LDH effectively neutralizes the most of the
acidic lysosomes or autophagolysosomes in tumor cells within 4 h, and the intervention effect lasts
for at least 24 h (Figure S11  ). These results indicate that Zn-LDH can
effectively block the autophagic flux by inhibiting the acidification of autophagolysosomes.
--
  -            
         -  

 
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Figure 2. -   
   of 2,7-dichlorofluorescein diacetate (DCFH-DA, cellular ROS indicator)
staining-
--- -      
-
 CLSM images of the colocalization of Zn-LDH with autophagolysosomes in B16F10 cells
after incubation for 4 or 24 h-

- LDH, Zn-LDH and chloroquine (CQ) for 24 h. The
ratio of LC3-II/I is calculated by comparing their band densities, and the ratio of LC3-II/I in saline
group is defined as 1.00.           -

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
--
      high-mobility group box 1 protein
(HMGB1), adenosine triphosphate (ATP) and calreticulin (CRT).[29] 
       -       Figure 3
 -and -
     1.3 folds    
. Furthermore, --
                 

              
  -
-
 -          
- Information-
- ICD (indicated by        

-
--
-
        
 M     during ICD     
--
 -  
 -    
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--
           

Figure 3. -in B16F10 tumor
cells treated with ZnCl2, LDH, and Zn-LDH. Quantitative analysis of the ATP release in B16F10
tumor cells treated with ZnCl2, LDH, and Zn-LDH. (c-f) -
-                -
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Phagocytosis of dying B16F10 cells by DC2.4 (g) and Raw264.7 (h).
(j-k) The antigen-presentation by DCs
(j) and macrophages (k) in tdLNs. 
-
2.3. Zn-LDH Modulates Immunosuppressive TME to Potentiate Tumor Metalloimmunotherapy
-
--
---
-
---
    - -     

-
         -   
            
-

-
              

           
-      -    

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--
             
-

        -         
-
--
--
-
-      -    
-
 -
-  
-

-
--
-
        --     
-
        -
-

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Figure 4. --

-

---
--
-
   -- TME          
-
2.4. Zn-LDH Inhibits the Growth of Malignant Tumors
--
Figure 5
--

         -   
 - -
--
 -
             

 --
-           -  
         -     
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-

-
-
--
  -         

          --     
-
             

      -    
-
    

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Figure 5. -
               

   -             
              
                
-


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
-


-

3. Conclusion
-  
       - 
        -     
-  -
           -  
             -
   
-          -

 -
 -          
            
 -
              
-
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           

          -
          
            
-
           
-
          
 
      
ZnO, Zn-based metal-organic frameworks and ZnS) effectively induces tumor ICD by generating
tumor antigens or activating cGas-STING signaling pathway      -
          
-           

-


-
   
--
  
-
            
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     -      
     diverse LDH immunomodulating adjuvants containing
these specific divalent cations are expected to effectively activate TME and evoke potent cancer
metalloimmunotherapy
 
--
-
               

            - 
           
-
   -          
 
 -          - 
             
 -        
           

Supporting Information
Supporting Information is available from the Wiley Online Library or from the author.
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25
Acknowledgements
L.Z., J.Z., X.H. and C.W. contributed equally to this work.     
          
 
--
             
          
the Innovative Research Team
of High-Level Local Universities in Shanghai (SHSMU-ZDCX20210900),
         

-
Conflict of Interest

Data Availability Statement
  

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Revised: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
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A simple yet robust immunomodulating adjuvant of Zn2+-doped layered double hydroxide (Zn-LDH) is
developed to potentiate cancer metalloimmunotherapy without using any cytotoxic inflammatory
cytokines or immune agonists. Peritumorally injected Zn-LDH simultaneously modulates
immunosuppressive tumor microenvironment and induces tumor immunogenic cell death, eliciting
robust antitumor immunity.
Lingxiao Zhang, Jing Zhao, Xi Hu, Chenhan Wang, Yingbo Jia, Chaojie Zhu, Shangzhi Xie, Jiyoung Lee,
Fangyuan Li*, and Daishun Ling*
A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe
Metalloimmunotherapy Against Solid Tumors
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Early diagnosis of acute liver failure (ALF) is critical for a curable treatment of the patients, because most existing ALF therapies have narrow therapeutic time windows after disease onset. Reactive oxygen species (ROS), which lead to the sequential occurrences of hepatocyte necrosis and the leakage of alanine aminotransferase (ALT), represent early biomarkers of ALF. Photoacoustic imaging is emerging as a powerful tool for in vivo imaging of ROS. However, high-performance imaging probes that can boost the photoacoustic signals of short-lived ROS of ALF are yet to be developed, and there remains a great challenge for ROS-based imaging of ALF. Herein, we present a ROS-sensitive nanozyme-augmented photoacoustic nanoprobe for successful in vivo imaging of ALF. The deep-penetrated photoacoustic signals of nanoprobe can be activated by the overexpressed ROS in ALF due to the synergy between nanocatalytic bubbles generation and thermoelastic expansion. Impressively, the nanozyme-augmented ROS imaging enables earlier diagnosis of ALF than clinical ALT method, and the ROS-activated catalytic activity of nanoprobe permits timely nanocatalytic therapy of ALF. This article is protected by copyright. All rights reserved
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Laser Ablation: Heating up the Anti-Tumor Response in the Intracranial Compartment
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  • Apr 2022
  • ADV DRUG DELIVER REV
Immunotherapies, such as immune checkpoint inhibition (ICI), have had limited success in treating intracranial malignancies. These failures are due partly to the restrictive blood-brain-barrier (BBB), the profound tumor-dependent induction of local and systemic immunosuppression, and immune evasion exhibited by these tumors. Therefore, novel approaches must be explored that aim to overcome these stringent barriers. LITT is an emerging treatment for brain tumors that utilizes thermal ablation to kill tumor cells. LITT provides an additional therapeutic benefit by synergizing with ICI and systemic chemotherapies to strengthen the anti-tumor immune response. This synergistic relationship involves transient disruption of the BBB and local augmentation of immune function, culminating in increased CNS drug penetrance and improved anti-tumor immunity. In this review, we will provide an overview of the challenges facing immunotherapy for brain tumors, and discuss how LITT may synergize with the endogenous anti-tumor response to improve the efficacy of ICI.
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The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy
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  • Jan 2022
Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans. The application of natural cytokines in clinical studies has not been clearly established, and there are often problems associated with toxicity or lack of efficacy. The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells. With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions, artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach. Engineered cytokines are designed to selectively target cells. Herein, the theoretical and experimental evidence of cytokine engineering is reviewed, and the “supercytokines” resulting from structural enhancement and the “immunocytokines” generated by antibody fusion are described. Finally, the “engager cytokines” formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.
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Clinical Translation of Nanomedicines: Challenges, Opportunities, and Keys
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  • Feb 2022
  • ADV DRUG DELIVER REV
Despite the massive interest and recent developments in the field of nanomedicine, only a limited number of formulations have found their way to the clinics. This shortcoming reveals the challenges facing the clinical translation of this technology. In the current article, we summarize and evaluate the status, market situation, and clinical profiles of the reported nanomedicines, the shortcomings limiting their clinical translation, as well as some approaches designed to break through this barrier. Moreover, some emerging technologies that have the potential to compete with nanomedicines are highlighted. Lastly, we identify the key factors that should be considered in nanomedicine-related research to be clinically-translatable. These can be classified into five areas: rational design during the research and development stage, the recruitment of representative preclinical models, careful design of clinical trials, development of specific and uniform regulatory protocols, and calls for non-classic sponsorship. This new field of endeavor was firmly established during the last two decades and more in-depth progress is expected in the coming years.
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