Immunomodulatory carbon dots balance the anti-inflammatory, antibacterial, and osteogenic activities of metal-phenolic network for osteomyelitis therapy.

The treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) infection is severely hindered by the challenges of bacterial infection, excessive inflammation, and impaired osteogenesis. To address these challenges, we first develop an integrated nanoplatform (Se-CD@Cu-EGC) with concurrent anti-inflammatory, antibacterial, and osteogenic activities based on metal-phenolic networks (MPNs) and selenium-doped carbon dots (Se-CDs). Initially, a systematic investigation into the structure-activity relationship of MPNs is conducted using five polyphenol compounds with different numbers of phenolic hydroxyl groups. This reveals that Cu-EGC, assembled from Cu and (-)-epigallocatechin (EGC), possesses suitable pH-responsive degradation behaviors and exhibits strongest antibacterial activity owing to the synergistic membrane disruption and cuproptosis-like death. To further endow Cu-EGC with anti-inflammatory and osteogenic activities, Se-CDs with both immune regulation and osteogenic activity are loaded on Cu-EGC to form Se-CD@Cu-EGC nanoplatforms. The doping of Se element in CDs not only endows CDs with ROS scavenging performance and anti-inflammatory ability through reprogramming macrophages from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype, but also optimizes the surface charge state of CDs to activate BMP/Smad pathway for promoting osteogenic differentiation of BMSCs. Se-CD@Cu-EGC is then incorporated into GelMA hydrogel for the eradicating biofilms, mitigating inflammation, and promoting bone repair in a MRSA-induced osteomyelitis model. This work not only elucidates the precise influence of polyphenol structure on the antibacterial activity of MPNs but also presents a novel strategy for the rational design of multifunctional biomaterials against infectious osteomyelitis.