Modifying MSCs-derived EVs with esterase-responsive and charge-reversal cationic polymers enhances bone regeneration

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) for the treatment of bone defects have been widely reported as a cell-free therapy because of their appropriate stability and biocompatibility. However, EV isolation is expensive and time-consuming. We developed a method of modifying EVs derived from bone marrow MSCs (BMSCs) via the cationic polymer (ERP) with characteristics of charge reversal and esterase response (ERP-EVs). When simply mixing BMSCs-EVs with ERP at a 1:1 ratio, ERP-EVs significantly enhanced the osteogenesis of BMSCs. More EVs were released by ERP in BMSCs than in fibroblasts, realizing the selective release. Last, ERP-EVs were loaded on an nHA/CS-MS scaffold and showed enhanced bone regeneration on rat calvarial bone defects in vivo. In general, this study provided an effective strategy to improve cellular uptake and selective release of BMSCs-EVs in bone-related cells, which had great potential to accelerate the clinical practice of BMSCs-EVs-based bone defect repair.