Self-sacrificing templated-derived chitosan microcapsules for targeted drug delivery in thrombolytic therapy

Thromboembolic diseases are a major global health threat. Yet current thrombolytic therapies remain limited by systemic off-target effects, short drug half-life, and poor thrombus penetrability. Herein, we report a self-sacrificing template strategy that enables simultaneous microcapsule assembly and template degradation, resulting in the formation of hollow chitosan microcapsules (CSMs) without the need for post-assembly template removal. The microcapsules obtained are then employed to cure thrombosis-related diseases. Using CaCO₃ microparticles (CMPs) as templates, water-soluble chitosan (CS) is assembled onto porous CMP preloaded with recombinant tissue plasminogen activator (rt-PA) under controlled conditions, which triggers CMP dissolution while retaining rt-PA within the CSMs. Subsequently, CSMs are modified with fibrin-targeting CREKA peptides to produce rt-PA@CSMs-CREKA, which possess an optimal microscale size for overcoming margination effects. These microcapsules exhibit high drug loading, favorable biocompatibility, and prolonged circulation time. Both in vitro and in vivo studies demonstrate that rt-PA@CSMs-CREKA achieves superior thrombus targeting, site-specific drug accumulation, and enhanced penetration, effectively degrading fibrin networks and dissolving thrombotic clots. Compared with free rt-PA, rt-PA@CSMs-CREKA possesses significantly enhanced thrombolytic efficacy while downregulating key coagulation factors (FXa and PAI-1). This study presents a promising targeted delivery platform for thrombolytic therapy and offers a novel approach for fabricating CS-related polymeric microcapsules.