The clinical failure of conventional osteomyelitis treatments often arises from their inability to concurrently eradicate biofilms, resolve chronic inflammation, and promote bone repair. Therefore, there is an urgent need for a therapeutic approach that simultaneously addresses infection, immune dysregulation, and tissue loss. This study aims to develop a multifunctional nanocomposite hydrogel (AsCu@Gel) that integrates antibacterial, immunomodulatory, and osteoinductive properties for the comprehensive treatment of acute Staphylococcal osteomyelitis (AOM). We engineered a thermosensitive hydrogel encapsulating Astaxanthin-Copper nanoparticles (AsCu@NPs). The material was characterized for its structure, multi-stimuli responsive release (pH, enzyme, temperature), and biocompatibility. Its efficacy was evaluated through in vitro antibacterial and anti-biofilm assays, analysis of macrophage polarization, and osteogenic differentiation studies. A mouse model of implant-associated AOM was used to validate the in vivo therapeutic effects, immune modulation, and bone preservation. The AsCu@Gel system demonstrated potent, pH-enhanced antibacterial and anti-biofilm activity. Crucially, it synergistically polarized macrophages from a pro-inflammatory M1 to a pro-healing M2 phenotype, significantly elevating IL-10, ARG1, and CD206 while suppressing TNF-α, IL-6, and iNOS. Network pharmacology and experimental validation revealed that this dual action downregulated key inflammatory pathways (e.g., TLR9, MAPK8) and upregulated osteogenic signals (e.g., AKT1). In vivo, AsCu@Gel effectively eradicated infection, resolved systemic and local inflammation, and preserved bone architecture, outperforming monotherapy controls. The AsCu@Gel platform represents a shift from simple antibacterial treatment to a comprehensive strategy of anti-infection, anti-inflammatory, and pro-regeneration. Simultaneously disrupting biofilms and reprogramming the immune microenvironment toward regeneration offers a promising and innovative solution for treating complex bone infections.

The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis (OA) remain unknown. No pharmacological intervention can currently prevent the progression of osteoarthritis. Accumulating evidence has shown that subchondral bone deterioration is a primary trigger for overlying cartilage degeneration. We previously found that H-type vessels modulate aberrant subchondral bone formation during the pathogenesis of OA. However, the mechanism responsible for the elevation of H-type vessels in OA is still unclear. Here, we found that PDGFR-β expression, predominantly in the CD31^hiEmcn^hi endothelium, was substantially elevated in subchondral bones from OA patients and rodent OA models. A mouse model of OA with deletion of PDGFR-β in endothelial cells (ECs) exhibited fewer H-type vessels, ameliorated subchondral bone deterioration and alleviated overlying cartilage degeneration. Endothelial PDGFR-β promotes angiogenesis through the formation of the PDGFR-β/talin1/FAK complex. Notably, endothelium-specific inhibition of PDGFR-β by local injection of AAV9 in subchondral bone effectively attenuated the pathogenesis of OA compared with that of the vehicle-treated controls. Based on the results from this study, targeting PDGFR-β is a novel and promising approach for the prevention or early treatment of OA.