Self-boosting stimulus activation of a polyprodrug with cascade amplification for enhanced antitumor efficacy.

The use of polyprodrugs, which bind drugs to polymer chains through responsive linkers, is a potential technique for cancer therapy; however, a lack of endogenous triggering factors limits drug activation in tumor tissue. Herein, we rationally created a reactive oxygen species (ROS)-sensitive polyprodrug (TS CA/DOX ) with cascade amplification of triggering agents and drug activation by incorporating both an ROS signal amplifier (TA CA ) and a drug activation amplifier (SIP DOX ) into a delivery system. Endogenous ROS as a triggering mechanism kicked off the initial circulation phase to increase intracellular ROS signals. Subsequently, the enhanced ROS initiated the second degradation step, allowing the polyprodrug SIP DOX to fracture spontaneously in a domino-like fashion, resulting in self-accelerated drug activation in tumor tissue. Therefore, the polyprodrug created in this study with cascade amplification of drug activation holds great promise for effective cancer treatment.