Hypoxia-Adaptive Confined Cascade Nanoplatform Unleashing ROS/RNS Storm and Metal Ions to Orchestrate Necroptosis, Ferroptosis, and cGAS-STING Immunity.

Abstract

The hypoxic and immunosuppressive tumor microenvironment limits photodynamic therapy (PDT) and antitumor immunity. To address this, we construct a hypoxia-adaptive nanoplatform PG@Mn-ZIF8 by co-encapsulating a J-aggregating platinum photosensitizer Pt-3T and the nitric oxide (NO) donor S-nitrosoglutathione (GSNO) within Mn²⁺/Zn²⁺ doped ZIF-8. This nanoplatform can decompose endogenous H₂O₂ to O₂ via Pt aggregate-mediated catalase (CAT)-mimetic activity, alleviating hypoxia before light irradiation. Upon illumination, Pt-3T generates a robust Type I/II reactive oxygen species (ROS) storm, which triggers rapid NO release from GSNO, and further convert ROS and NO into highly cytotoxic peroxynitrite (ONOO^•-), thereby amplifying an ROS/RNS storm within the confined MOF space. This co storm disrupts redox homeostasis to induce both necroptosis and ferroptosis alongside immunogenic cell death (ICD). Moreover, the released Mn²⁺ and Zn²⁺ upon MOF degradation synergistically potentiate the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway. Consequently, the spatiotemporal "O₂-ROS/RNS-metal ions" cascade enables the nanoplatform to trigger multimodal cell death and ignite cGAS-STING-driven innate and adaptive immunity, eradicating solid tumors, establishing long-term immune memory, and reversing the "cold" tumor phenotype.