Citation: Huijuan Zhang, Chenglin Liang, Xinyi Ding, Meng Zhang, Siyu Lu, Lin Hou. Manganese-based nano-delivery system for sensitized anti-tumor immunotherapy via combined autophagy inhibition[J]. Chinese Chemical Letters, ;2025, 36(7): 110525. doi: 10.1016/j.cclet.2024.110525 shu

Manganese-based nano-delivery system for sensitized anti-tumor immunotherapy via combined autophagy inhibition

Huijuan Zhang ^{a, b, 1} ,
Chenglin Liang ^{a, 1} ,
Xinyi Ding ^a ,
Meng Zhang ^a ,
Siyu Lu ^{c, *,} ,
Lin Hou ^{a, b, *,}

a.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
b.
Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou 450001, China
c.
Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou 450001, China

sylu2013@zzu.edu.cn

houlin_pharm@163.com

Received Date: 20 August 2024
Revised Date: 27 September 2024
Accepted Date: 3 October 2024
Available Online: 5 October 2024

Figures(5)

The stimulator of interferon genes (STING) agonists have been widely applied to active cyclic guanosine monophophate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-STING signaling for tumor immunotherapy. However, the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment (TME). In this study, we constructed a manganese-based nano drug delivery system (NDDS) loaded with hydroxychloroquine (HCQ) for synergistic autophagy inhibition and STING activation-based immunotherapy. Hyaluronic acid (HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis. Subsequently, it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn²⁺ and HCQ simultaneously. As a kind of STING agonist, Mn²⁺ can bind to cGAS in tumor cells, activating the cGAS-STING pathway and generating type Ⅰ-interferons (IFN-Ⅰ), which helped alleviate the immunosuppressive TME. Meanwhile, HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation, further sensitizing the cGAS-STING signal. Benefiting from this synergistic mechanism, HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment. Moreover, HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis. This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.
- Anti-tumor immunotherapy,
- cGAS-STING signaling,
- Mn²⁺ and HCQ co-delivery,
- Autophagy inhibition,
- TME responsive
1. [1]
  Y. Zhou, J. Yuan, K. Xu, et al., ACS Nano 18 (2024) 1846–1864. doi: 10.1021/acsnano.3c11260
2. [2]
  E. Chin, A. Sulpizio, L. Lairson, Trends Cell Biol. 33 (2023) 189–203.
3. [3]
  Y. Huang, H. Fan, H. Ti, Asian J. Pharm. Sci. 19 (2024) 100902.
4. [4]
  X. Wang, Y. Liu, C. Xue, et al., Nat. Commun. 13 (2022) 5685.
5. [5]
  L. Liu, H. Lei, G. Hou, et al., ACS Nano 18 (2024) 12830–12844. doi: 10.1021/acsnano.4c00017
6. [6]
  J. Yang, Y. He, M. Zhang, et al., Exploration 3 (2023) 20230061.
7. [7]
  B. Zhao, P. Xu, C. Shu, et al., Nature 569 (2019) 718–722. doi: 10.1038/s41586-019-1228-x
8. [8]
  N. Samson, A. Ablasser, Nat. Cancer 3 (2022) 1452–1463. doi: 10.1038/s43018-022-00468-w
9. [9]
  S. Liang, J. Yao, D. Liu, et al., Chin. Chem. Lett. 36 (2025) 109856. doi: 10.1016/j.cclet.2024.109856
10. [10]
  R. Zhang, R. Kang, D. Tang, Sig. Transduct, Target. Ther. 6 (2021) 208.
11. [11]
  K. Hopfner, V. Hornung, Nat. Rev. Mol. Cell Biol. 21 (2020) 501–521. doi: 10.1038/s41580-020-0244-x
12. [12]
  L. Ou, Y. Cheng, Y. Chen, Front. Immunol. 12 (2021) 759048.
13. [13]
  H. Yang, S. Yang, Q. Guo, et al., Adv. Mater. 36 (2024) e2310189.
14. [14]
  X. Liu, F. Chen, M. Saeed, et al., Nano Today 56 (2024) 102273.
15. [15]
  M. Lv, R. Zhang, W. Zhang, et al., Cell Res. 30 (2020) 966–979. doi: 10.1038/s41422-020-00395-4
16. [16]
  W. Qiao, J. Chen, H. Zhou, et al., Adv. Sci. 11 (2024) e2305979.
17. [17]
  D. Chen, L. Hou, Y. Yan, et al., ACS Nano 14 (2020) 3927–3940. doi: 10.1093/bioinformatics/btaa205
18. [18]
  M. Pan, Y. Yin, T. Hu, et al., Autophagy 19 (2022) 440–456.
19. [19]
  Y Wang, Ramos M, M. Jefferson, et al., Sci. Adv. 8 (2022) eabn3298.
20. [20]
  D. Liu, H. Wu, C. Wang, et al., Cell Death Differ. 26 (2018) 1735–1749.
21. [21]
  X. Gui, H. Yang, T. Li, et al., Nature 567 (2019) 262–266. doi: 10.1038/s41586-019-1006-9
22. [22]
  H. Zhang, L. Zhang, Z. Cao, et al., Small 18 (2022) e2200299.
23. [23]
  W. Chen, J. Ouyang, H. Liu, et al., Adv. Mater. 29 (2016) 1603864.
24. [24]
  L. Gao, Y. Song, J. Zhong, et al., ACS Biomater. Sci. Eng. 8 (2022) 1074–1086. doi: 10.1021/acsbiomaterials.1c01430
25. [25]
  Y. Wu, Z. Zhang, Y. Wei, et al., Chin. Chem. Lett. 34 (2023) 108098.
26. [26]
  P. Sun, Z. Li, D. Zhang, et al., Chin. Chem. Lett. 35 (2024) 108346.
1. [1]
  Qianyun Ye , Yuanyuan Liang , Yuhe Yuan , Xiaohuan Sun , Liqi Zhu , Xuan Wu , Jie Han , Rong Guo . pH-responsive chiral supramolecular cysteine-Zn²⁺-indocyanine green assemblies for triple-level chirality-specific anti-tumor efficacy. Chinese Chemical Letters, 2025, 36(5): 110432-. doi: 10.1016/j.cclet.2024.110432
2. [2]
  Shuang Liang , Jianjun Yao , Dan Liu , Mengli Zhou , Yong Cui , Zhaohui Wang . Tumor-responsive covalent organic polymeric nanoparticles enhancing STING activation for cancer immunotherapy. Chinese Chemical Letters, 2025, 36(3): 109856-. doi: 10.1016/j.cclet.2024.109856
3. [3]
  Yunjie Dang , Yanru Feng , Xiao Chen , Chaoxing He , Shujie Wei , Dingyang Liu , Jinlong Qi , Huaxing Zhang , Shaokun Yang , Zhiyun Niu , Bai Xiang . Development of a multi-level pH-responsive lipid nanoplatform for efficient co-delivery of siRNA and small-molecule drugs in tumor treatment. Chinese Chemical Letters, 2024, 35(12): 109660-. doi: 10.1016/j.cclet.2024.109660
4. [4]
  Li Fu , Ziye Su , Shuyang Wu , Yanfen Cheng , Chuan Hu , Jinming Zhang . Redox-responsive hyaluronic acid-celastrol prodrug micelles with glycyrrhetinic acid co-delivery for tumor combination therapy. Chinese Chemical Letters, 2025, 36(5): 110227-. doi: 10.1016/j.cclet.2024.110227
5. [5]
  Yuanyi Zhou , Ke Ma , Jinfeng Liu , Zirun Zheng , Bo Hu , Yu Meng , Zhizhong Li , Mingshan Zhu . Is reactive oxygen species the only way for cancer inhibition over single atom nanomedicine? Autophagy regulation also works. Chinese Chemical Letters, 2024, 35(6): 109056-. doi: 10.1016/j.cclet.2023.109056
6. [6]
  Yi Cao , Xiaojiao Ge , Yuanyuan Wei , Lulu He , Aiguo Wu , Juan Li . Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition. Chinese Chemical Letters, 2024, 35(4): 108672-. doi: 10.1016/j.cclet.2023.108672
7. [7]
  Chanqi Ye , Jia Zhang , Jie Shen , Ruyin Chen , Qiong Li , Peng Zhao , Dong Chen , Jian Ruan . Attractive Pickering emulsion gel loaded with oxaliplatin and lactate dehydrogenase inhibitor increases the anti-tumor effect in hepatocellular carcinoma. Chinese Chemical Letters, 2025, 36(7): 110519-. doi: 10.1016/j.cclet.2024.110519
8. [8]
  Fanxin Kong , Hongzhi Wang , Huimei Duan . Inhibition effect of sulfation on Pt/TiO2 catalysts in methane combustion. Chinese Journal of Structural Chemistry, 2024, 43(5): 100287-100287. doi: 10.1016/j.cjsc.2024.100287
9. [9]
  Jiaqi Huang , Renjiang Kong , Yanmei Li , Ni Yan , Yeyang Wu , Ziwen Qiu , Zhenming Lu , Xiaona Rao , Shiying Li , Hong Cheng . Feedback enhanced tumor targeting delivery of albumin-based nanomedicine to amplify photodynamic therapy by regulating AMPK signaling and inhibiting GSTs. Chinese Chemical Letters, 2024, 35(8): 109254-. doi: 10.1016/j.cclet.2023.109254
10. [10]
  Chenlu Huang , Xinyu Yang , Qingyu Yu , Linhua Zhang , Dunwan Zhu . Gas-generating polymersomes-based amplified photoimmunotherapy for abscopal effect and tumor metastasis inhibition. Chinese Chemical Letters, 2024, 35(6): 109680-. doi: 10.1016/j.cclet.2024.109680
11. [11]
  Yuanzheng Wang , Chen Zhang , Shuyan Han , Xiaoli Kong , Changyun Quan , Jun Wu , Wei Zhang . Cancer cell membrane camouflaged biomimetic gelatin-based nanogel for tumor inhibition. Chinese Chemical Letters, 2024, 35(11): 109578-. doi: 10.1016/j.cclet.2024.109578
12. [12]
  Yanfei Liu , Yaqin Hu , Yifu Tan , Qiwen Chen , Zhenbao Liu . Tumor acidic microenvironment activatable DNA nanostructure for precise cancer cell targeting and inhibition. Chinese Chemical Letters, 2025, 36(1): 110289-. doi: 10.1016/j.cclet.2024.110289
13. [13]
  Yanjun Cai , Yong Jiang , Yu Chen , Erzhuo Cheng , Yuan Gu , Yuwei Li , Qianqian Liu , Jian Zhang , Jifang Liu , Shisong Han , Bin Yang . Amplifying STING activation and immunogenic cell death by metal-polyphenol coordinated nanomedicines for enhanced cancer immunotherapy. Chinese Chemical Letters, 2025, 36(5): 110437-. doi: 10.1016/j.cclet.2024.110437
14. [14]
  Yuanyuan Zeng , Fang Liu , Jun Wang , Bianfei Shao , Tao He , Zhongzheng Xiang , Yan Wang , Shunyao Zhu , Tian Yang , Siting Yu , Changyang Gong , Lei Liu . Fisetin micelles precisely exhibit a radiosensitization effect by inhibiting PDGFRβ/STAT1/STAT3/Bcl-2 signaling pathway in tumor. Chinese Chemical Letters, 2025, 36(2): 109734-. doi: 10.1016/j.cclet.2024.109734
15. [15]
  Jiayin Zhou , Depeng Liu , Longqiang Li , Min Qi , Guangqiang Yin , Tao Chen . Responsive organic room-temperature phosphorescence materials for spatial-time-resolved anti-counterfeiting. Chinese Chemical Letters, 2024, 35(11): 109929-. doi: 10.1016/j.cclet.2024.109929
16. [16]
  Jingqi Xin , Shupeng Han , Meichen Zheng , Chenfeng Xu , Zhongxi Huang , Bin Wang , Changmin Yu , Feifei An , Yu Ren . A nitroreductase-responsive nanoprobe with homogeneous composition and high loading for preoperative non-invasive tumor imaging and intraoperative guidance. Chinese Chemical Letters, 2024, 35(7): 109165-. doi: 10.1016/j.cclet.2023.109165
17. [17]
  Shupeng Han , Caiting Deng , Meichen Zheng , Linwei Yang , Hancun Kong , Yongchao He , Yinuo Zheng , Guowei Deng , Yu Ren , Feifei An . A GSH-responsive NIR-BODIPY fluorophore with large Stokes-shift for tumor specific fluorescence imaging and surgical guidance. Chinese Chemical Letters, 2025, 36(7): 110459-. doi: 10.1016/j.cclet.2024.110459
18. [18]
  Fan JIA , Wenbao XU , Fangbin LIU , Haihua ZHANG , Hongbing FU . Synthesis and electroluminescence properties of Mn²⁺ doped quasi-two-dimensional perovskites (PEA)₂Pb_yMn_1-yBr₄. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1114-1122. doi: 10.11862/CJIC.20230473
19. [19]
  Qilin YU , Yifei XU , Pengjun ZHANG , Shuwei HAO , Chongqiang ZHU , Chunhui YANG . Effect of regulating K⁺/Na⁺ ratio on the structure and optical properties of double perovskite Cs₂NaBiCl₆: Mn²⁺. Chinese Journal of Inorganic Chemistry, 2025, 41(6): 1058-1067. doi: 10.11862/CJIC.20240418
20. [20]
  Ruifeng Liang , Yanbei Tu , Peng Hua , Yongzhuo Huang , Meiwan Chen . ROS-responsive micelles co-loaded dexamethasone and pristimerin to restore the homeostasis of the inflammatory microenvironment for rheumatoid arthritis therapy. Chinese Chemical Letters, 2025, 36(6): 110335-. doi: 10.1016/j.cclet.2024.110335

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(5)
HTML views(1)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142