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

Abstract 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.