Oxaliplatin/Norcantharidin Prodrug Co‐Loaded Nanoparticles: Synergistic DNA‐Repair Blockade Plus PD‐L1 Downregulation for Inhibit Tumor Growth and Metastasis

ABSTRACT The combination of phototherapy with oxaliplatin (OXA) represents a potent strategy for triggering immunogenic cell death (ICD) and elicit robust antitumor immunity. In this study, we construct IROTD nanoparticles (IROTD NPs) through self‐assembly of a norcantharidin (NCTD)‐OXA‐conjugated polymer (P2) and the near‐infrared (NIR) photosensitizer DTIR780. Under 808 nm laser irradiation, IROTD NPs generate heat and reactive oxygen species (ROS) while release OXA and NCTD, result in severe DNA damage and potent induction of ICD within tumor cells. Concurrently, NCTD inhibits DNA repair mechanisms and down‐regulates PD‐L1expression, thereby increase the infiltration of cytotoxic T‐cell and amplify systemic antitumor immunity. Leverage the enhanced permeability and retention (EPR) effect, IROTD NPs efficiently accumulate at tumor sites, result in remarkable inhibition of tumor growth and recruitment of CD4 + and CD8 + T lymphocytes, which collectively contribute to the activation of a systemic antitumor immunity. In a bilateral tumor model, IROTD NPs effectively inhibit both primary and distant tumor growth. Overall, this work presents a rationally designed combinatorial nanoplatform that effectively ignites systemic immune response, thus establish a prospective chemo‐immunotherapeutic stratagem for cancer treatment.