Tumor‐Specific On‐Site Activation of Cisplatin via Cascade Catalytic‐Redox Reactions for Highly Efficient Chemo‐Immunotherapy

The therapeutic efficiency of platinum drugs is always limited by low utilization, side effects, and Pt-resistance. Herein, a double-lock protected Pt^II nanomedicine named PtNP@Cu has been developed, which performs cascade unlocking of dechlorinated cisplatin (DP) via catalytic-redox reactions, thus achieving tumor-specific "on-site" activation of cisplatin (cDDP) in the nucleus accompanied with substantial induction of ferroptosis of cancer cells. This design avoids the premature release of active Pt^II species in normal cells or in the cytoplasm of cancer cells before reaching nucleus, thereby ensuring maximum amplification of Pt-DNA crosslinking with tumor-specificity. Meanwhile, substantial GSH depletion and ROS production induced by cascade catalytic-redox reactions results in ferroptosis of cancer cells, which further reduces GSH-mediated cDDP detoxification, overcomes Pt-resistance, and enhances immunogenicity, ultimately realizing highly efficient tumor-specific chemotherapy and antitumor immunity in vivo. This work provides a new strategy for effectively and comprehensively addressing the issues of low utilization, side effects, and drug resistance problems of platinum drugs, which is also promising for chemo-immunotherapy.