Zhao_2026_J.Control.Release__114849

Chemodynamic therapy (CDT) has been widely explored for the treatment of various solid tumors. However, its efficacy is severely limited by insufficient reactive oxygen species (ROS) amplification and epigenetic silencing of key immune-regulatory genes. Herein, we developed a composite nanovesicle (PLMD) that integrates CDT with epigenetic reprogramming to synergistically activate the cGAS-STING pathway and induce pyroptosis. PLMD was constructed via amphiphilic polymer self-assembly and surface-functionalization with sialic acid to enhance tumor targeting, enabling the co-delivery of beta-lapachone (Lap), Mn(2+), and decitabine (Dac) with acid- and carboxylesterase-responsive release in tumor cells. Lap selectively generates H(2)O(2) in NQO1-overexpressing tumor cells, which cooperates with Mn(2+)-mediated Fenton-like reactions to amplify intracellular ROS level, induce mitochondrial damage, and promote cytosolic mitochondrial DNA (mtDNA) release. Mn(2+) further sensitizes cGAS DNA sensing, leading to robust activation of the cGAS-STING signaling pathway. Meanwhile, activation of the intrinsic apoptotic pathway induces caspase-3 cleavage of gasdermin E (GSDME), thereby inducing pyroptosis. Furthermore, Dac epigenetically restores the expression of STING and GSDME via DNA demethylation, markedly augmenting cGAS-STING activation and pyroptosis. As a result, PLMD treatment enhances dendritic cell maturation and T-cell priming, ultimately achieving pronounced tumor growth inhibition and robust antitumor immune responses in a 4T1 tumor model.