On-Site Self-Penetrating Nanomedicine Enabling Dual-Priming Drug Activation and Inside-Out Thrombus Ablation

Main conventional antithrombotic therapies often suffer from unsatisfactory treatment outcomes and the risk of undesirable tissue hemorrhage. Deep clot penetration, on-demand drug activation, and release within the clots remain significant challenges. While past efforts to develop nanomedicines and prodrugs have improved safety at the expense of therapeutic effects. Herein, we develop a self-piercing and self-activating nanoassembly composed of an oxidation-sensitive prodrug (TGL-S-Fmoc, TSF) of ticagrelor (TGL) and IR808 (a photothermal/photodynamic dual-effect photosensitizer). TSF readily coassembles with IR808 into a carrier-free hybrid nanomedicine. Upon laser irradiation, IR808 enables photothermal thrombolysis and deep clot penetration of TSF while also synergistically facilitating prodrug activation triggered by IR808-generated singlet oxygen (¹O₂) and the endogenous hydrogen peroxide within the clots. Following fibrin-targeting modification, the nanoassembly achieves self-indicating thrombus-targeted accumulation, self-piercing deep clot penetration, dual-priming prodrug activation, and inside-out thrombus ablation with favorable safety in vivo. This study advances the clinical translation of antithrombotic prodrugs and nanomedicines.