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

ABSTRACT Chemodynamic therapy (CDT) is severely limited by inadequate intracellular H 2 O 2 and frequent apoptosis resistance. Herein, a porous Fe 3 O 4 nanoplatform is engineered through coating of Fe 3 + ‐tannic acid complex onto nanoclusters simultaneously loaded with carbonyl cyanide 3‐chlorophenylhydrazone (CCCP, a mitochondrial uncoupler) and lactate oxidase (LOD). By self‐supplying H 2 O 2 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 Fe 2 + /Fe 3 + for Fenton reactions while LOD simultaneously converts lactate to H 2 O 2 , overcoming the H 2 O 2 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.