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GSH-Triggered Self-Cascading Nanoreactor Integrates Efficient ICD Induction and Immune Checkpoint Blockade for Pancreatic Cancer Therapy

Jingru Cui,Zhonghui Xue,Zhengxian Zhang,Huanhuan Zhu,Mingsan Miao,Yagang Song,Xiaofang Li,Huahui Zeng,Xiangxiang Wu

Chemodynamic therapy (CDT) is currently constrained by insufficient endogenous H 2 O 2 , enhanced antioxidant defense, weakly acidic conditions in pancreatic cancer. However, the CDT's immunotherapeutic potential hinges on radical-mediated immunogenic cell death (ICD) induction, motivating development of potent self-cascading radical nanogenerators. Herein, this work engineers carrier-free nanoparticles (IAA NPs) through metal-organic self-assembly of Fe 3+ , artesunate (AS) and PD-L1 antibody (αPD-L1), exhibiting high drug loading (AS: 80.62%, Fe 3+ : 4.57%, and αPD-L1: 14.81%), excellent stability and GSH/pH-dependent drug release. IAA NPs achieve GSH-triggered Fe 3+ reduction to Fe 2+ , catalyzing AS decomposition into carbon-centered radicals, with this radicalogenesis being H 2 O 2 /pH-independent while concurrently depleting intratumoral GSH antioxidant. These free radicals effectively induce ICD via apoptosis pathway, eliciting CRT exposure, HMGB1/ATP release, and efficient DC maturation. In Pan02 tumor-bearing mice, IAA NPs efficiently triggers ICD, promoting DC maturation, intratumoral CD4 + /CD8 + T-cell infiltration, and markedly inhibiting tumor growth. Concurrently, αPD-L1 blocks PD-1/PD-L1 pathway and restores T cell recognition, thereby enhancing the antitumor immune response. In addition, the favorable pharmacokinetic profiles, coupled with inherent biocompatibility and biosafety, collectively enhance IAA NPs’ translational potential. Basically, IAA NPs represent a novel strategy to improve combination chemodynamic-immunotherapy through radical-induced ICD and PD-L1 blockade.