Metal-polyphenol network-engineered mesenchymal stem cell-derived exosome mimetics mediate inflammatory/immune regulation for enhanced periodontal tissue regeneration.

Exosomes represent a promising therapeutic strategy in regenerative medicine; however, challenges such as unscalable production and poor tolerance to pathological host microenvironments impede their clinical translation. To address these limitations, this study developed bone marrow mesenchymal stem cell (BMSC)-derived exosome mimetics (EMs), produced through an optimized extrusion methodology, which enhanced production yield while preserving the core morphology and structure of natural exosomes with augmented functionality in key biological processes. Furthermore, these EMs are coated with a tannic acid (TA)/Fe3+ coordination network that acts as a protective barrier with antioxidative and antibacterial properties. This coating enables EMs to promote stem cell proliferation, migration, osteogenesis, and immunomodulation under inflammatory and oxidative stress conditions. In vivo, the local injection of EM@[TA-Fe3+] effectively suppressed periodontal inflammation and promoted alveolar bone regeneration. These findings advance our understanding of the structural and functional characteristics of EMs and present an efficient strategy for their delivery in bone regeneration especially under inflammatory and/or infectious conditions.