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
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沈阳化工大学材料科学与工程学院沈阳 110142