Citation: Yongjuan Li, Rongrong Zhu, Yichen Guo, Yayun Wang, Rong Ma, Kunru Ma, Yongxing Zhao, Weijing Yang. Sequential-gated transformable nanoprodrug potentiates antitumor immunity through TME modulation and STING activation[J]. Chinese Chemical Letters, ;2025, 36(9): 110704. doi: 10.1016/j.cclet.2024.110704 shu

Sequential-gated transformable nanoprodrug potentiates antitumor immunity through TME modulation and STING activation

Yongjuan Li ^{a, b} ,
Rongrong Zhu ^a ,
Yichen Guo ^a ,
Yayun Wang ^a ,
Rong Ma ^a ,
Kunru Ma ^a ,
Yongxing Zhao ^{a, *,} ,
Weijing Yang ^{a, *,}

a.
School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou 450001, China
b.
Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China

zhaoyx@zzu.edu.cn

wjyang@zzu.edu.cn

Received Date: 3 September 2024
Revised Date: 21 November 2024
Accepted Date: 2 December 2024
Available Online: 2 December 2024

Figures(5)

Nanomaterials that can sequentially respond to internal and external stimuli, functioning as a sequential gate, have great potential for targeting different aspects of antitumor immunity. Herein, we construct a mannose-modified, pH and reactive oxygen species (ROS) sequential-responsive, transformable dual-immunofunction nanoprodrug (MpRTNP). This nanoprodrug encapsulates a transforming growth factor-β (TGF-β) receptor inhibitor SD-208 (MpRTNP@SD), to simultaneously alleviate the immunosuppressive effects of TGF-β and tumor-associated macrophages (TAMs). In the weakly acidic tumor microenvironment (TME), the vesicle-micelle morphology transformation occurs owing to the protonation of PC7A, which is accompanied by SD-208 release to inhibit cancer-associated fibroblasts and regulatory T cells. The transformed micelles then target TAMs via mannose receptor-mediated endocytosis. Upon laser irradiation, the thioketal linker is cleaved, releasing conjugated chlorin e6 and generating ROS, which facilitates TAM polarization. The PC7A⁺ segment activates the stimulator of the interferon gene in TAMs with elevated phosphorylation of TANK binding kinase 1 and interferon regulatory factor 3, and type Ⅰ interferon secretion. MpRTNP@SD displays superior abscopal effects and robust antitumor immunity, as evidenced by increased CD8⁺/CD4⁺ T cell infiltration and reduced regulatory T cell (Treg) ratios. Mouse survival time is prolonged after combination with the CD47 antibody. This study provides a novel strategy for potent antitumor immunotherapy through pH and ROS sequential-gated spatiotemporal regulation of the TME.
- Drug delivery,
- Stimulus-responsive nanoprodrug,
- Tumor microenvironment modulation,
- STING activation,
- Cancer immunotherapy
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