Targeted Delivery of Exosomal Bmp2 mRNA via a Bioadhesive Interface Synergistically Enhances Titanium Implant Osseointegration

Abstract Rapid osseointegration of titanium implants remains challenging under pathological conditions. This study develops an engineered exosome‐based mRNA delivery system for osteogenic regulation. Through co‐transfection with BMP2 and Paip2 plasmids, Exosomes (Exo ^en ) loaded with untranslated Bmp2 mRNA are generated, exhibiting an eight‐fold increase over naive exosomes and a three‐fold enhancement compared to BMP2‐only exosomes. These vesicles are functionalized with a cholesterol‐anchored E7 peptide for BMSC targeting and immobilized on a titanium implant via a mussel adhesive protein coating (Exo ^en ‐E7@TiM). The system enables targeted, sustained delivery of Bmp2 mRNA to BMSCs. Once internalized, the mRNA utilizes an internal ribosome entry site (IRES) to initiate translation, effectively bypassing the original suppression and driving robust BMP2 protein expression. Exo ^en ‐E7@TiM significantly enhanced osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs) in vitro, upregulating key markers and accelerating mineralization. In rat tibiae, it substantially improved new bone formation and bone‐implant contact vs controls. This integrated strategy combines exosome‐mediated nucleic acid delivery, biological targeting, and bioadhesive immobilization to significantly enhance osseointegration, showing considerable promise for clinical applications in compromised bone healing.