miR-423-5p-enriched small extracellular vesicles drive periodontal regeneration via Sfrp2+ cell expansion

Small extracellular vesicles (sEVs) show therapeutic potential for periodontitis but functional components remain unclear, limiting clinical periodontal therapy application. Identifying key bioactive molecules and enhancing their functions via engineering strategies may overcome these limitations. By comparing the periodontal tropism of sEVs from different stem cells and conducting functional miRNA profiling, we identified miR-423-5p as a key component for periodontal ligament cell (PDLC) osteogenic differentiation by targeting <i>PLCB1</i> (Phospholipase C Beta 1). We engineered miR-423-5p-enriched sEVs (sEVs^miR-423-5p) with miRNA loading levels up to 100,000-fold higher than those of native sEVs. Compared with unmodified sEVs, sEVs^miR-423-5p promoted the formation of Sfrp2⁺ osteogenic fibroblasts at periodontal defect sites, ultimately facilitating early osteogenesis and regeneration of a native-like cementum-PDL-alveolar bone complex. These findings establish miR-423-5p as a pivotal osteoinductive effector in sEVs and demonstrate that its targeted enrichment markedly amplifies the regenerative capacity of sEVs, laying the groundwork for personalized nanovesicle-based regenerative therapies.