Gelated Apoptotic Extracellular Vesicles via Enzyme-Instructed Self-Assembly with Multifunctional Microcapsule for Targeted Atherosclerosis Therapy

Apoptotic extracellular vesicles (apoEVs) offer a cell-free approach to modulate macrophage-driven inflammation, but their applications are limited by cargo leakage, structural instability, and off-target effects. Herein, we developed engineered apoEVs by combining enzyme-instructed self-assembly (EISA) and surface modification techniques.

The hydrogel core formed within apoEVs via EISA enabled efficient encapsulation of atorvastatin while also improving vesicle stability. Concurrently, ROS/pH-responsive degradable microcapsules decorated on the apoEV surface enhanced plaque accumulation through hitchhiking and active targeting via the hyaluronic acid-CD44 interaction. Our engineered apoEVs demonstrated potent anti-atherosclerosis effects both in vitro and in vivo by inhibiting foam cell formation, inducing macrophage repolarization, restoring mitochondrial functions, and improving fibrous cap stability.