Delivery of Engineered BMP2 circRNA via Biomimetic Nanovesicles Enhances Titanium Implant Osseointegration Through Translation-Controlled Osteogenesis.

Abstract

Although mRNA therapy has achieved favorable outcomes, it still faces limitations such as poor stability and short duration of protein expression. In this study, we utilized a covalently closed circular RNA encoding bone morphogenetic protein-2 (BMP2 circRNA), which exhibits exceptional nuclease resistance and an extended half-life, thereby enabling sustained and efficient BMP2 protein expression. The BMP2 circRNA was encapsulated into biomimetic nanovesicles (BNVs) derived from bone marrow mesenchymal stem cells (BMSCs) using co-extrusion technology. These BNVs were then anchored onto the surface of micro-arc oxidized titanium (Ti-MAO) implants via polydopamine (PDA) adhesion, constructing a novel local gene delivery system. In vitro experiments confirmed that this system is not only efficiently internalized by cells but also evades lysosomal degradation, facilitating the sustained release of BMP2 protein. This, in turn, significantly promoted osteogenic gene expression and accelerated mineral deposition. Furthermore, in vivo animal studies demonstrated that the functionalized implant markedly enhanced bone regeneration, increasing both bone volume fraction and bone-to-implant contact. This study successfully integrated the inherent stability of circRNA with a biomimetic delivery strategy, offering an effective approach for improving implant osseointegration.