On-Site Self-Penetrating\nNanomedicine Enabling Dual-Priming\nDrug Activation and Inside-Out Thrombus Ablation

Main conventional antithrombotic therapies often suffer\nfrom unsatisfactory\ntreatment outcomes and the risk of undesirable tissue hemorrhage.\nDeep clot penetration, on-demand drug activation, and release within\nthe clots remain significant challenges. While past efforts to develop\nnanomedicines and prodrugs have improved safety at the expense of\ntherapeutic effects. Herein, we develop a self-piercing and self-activating\nnanoassembly composed of an oxidation-sensitive prodrug (TGL-S-Fmoc,\nTSF) of ticagrelor (TGL) and IR808 (a photothermal/photodynamic dual-effect\nphotosensitizer). TSF readily coassembles with IR808 into a carrier-free\nhybrid nanomedicine. Upon laser irradiation, IR808 enables photothermal\nthrombolysis and deep clot penetration of TSF while also synergistically\nfacilitating prodrug activation triggered by IR808-generated singlet\noxygen (<sup>1</sup>O<sub>2</sub>) and the endogenous hydrogen peroxide\nwithin the clots. Following fibrin-targeting modification, the nanoassembly\nachieves self-indicating thrombus-targeted accumulation, self-piercing\ndeep clot penetration, dual-priming prodrug activation, and inside-out\nthrombus ablation with favorable safety <i>in vivo</i>.\nThis study advances the clinical translation of antithrombotic prodrugs\nand nanomedicines.