Multi-Organelle Stress-Induced Paraptosis by a ROS-Amplifying Nanocatalyst for Enhanced Cancer Immunotherapy.

Chemodynamic therapy (CDT) is severely limited by inadequate intracellular H2O2 and frequent apoptosis resistance. Herein, a porous Fe3O4 nanoplatform is engineered through coating of Fe3 +-tannic acid complex onto nanoclusters simultaneously loaded with carbonyl cyanide 3-chlorophenylhydrazone (CCCP, a mitochondrial uncoupler) and lactate oxidase (LOD). By self-supplying H2O2 and concurrently blocking autophagic flux, this system is engineered to potentiate CDT efficacy. Beyond the expected therapeutic outcome, we uncover that this nanoplatform triggers an unconventional cell death pathway-paraptosis. Acid-triggered dissociation in the tumor microenvironment releases Fe2 +/Fe3 + for Fenton reactions while LOD simultaneously converts lactate to H2O2, overcoming the H2O2 bottleneck. CCCP further synergizes this process by collapsing the mitochondrial membrane potential, which amplifies ROS leakage and culminates in an oxidative storm. This dramatic surge in ROS directly induces mitochondrial dysfunction and initiates endoplasmic reticulum stress, while also suppressing autophagic flux. Collectively, these multi-organelle stresses markedly exacerbate intracellular damage and lead to paraptotic cell death, characterized by extensive cytoplasmic vacuolization, eliciting robust immunogenic cell death. Combined with αPD-L1, the nanoplatform potently activates antitumor immunity and suppresses both primary and distant tumors. This work pioneers a paraptosis activation strategy driven by an iron-based nanodrug, redefining CDT efficacy through multi-organelle stress synergy for amplified immunotherapy.