Propranolol-loaded multifunctional hydrogel enhances the repair of infected bone defects via sympathetic microenvironment remodelling

Infected bone defects pose a major challenge in orthopaedics, requiring simultaneous infection control and bone regeneration. Pathogen colonization initiates immune responses and acidic metabolite secretion, which suppress osteoblast function and may induce tissue necrosis. Meanwhile, traumatic injury activates systemic and local stress responses, leading to sympathetic overactivation and catecholamine accumulation in the defect area, further hindering bone repair. To address these issues, we developed a photosensitive gelatin methacryloyl (GelMA) hydrogel incorporating polydopamine (PDA)-coated hollow manganese dioxide (hMnO 2 ) nanoparticles loaded with propranolol (PNL), termed GMPP hydrogel. Under near-infrared light, GMPP generates photothermal effects that effectively kill Staphylococcus aureus and Escherichia coli . In the acidic infection microenvironment, propranolol is released, counteracting norepinephrine-mediated inhibition of angiogenesis and reducing excessive sympathetic nerve activity. Moreover, propranolol mitigates catabolic protein metabolism driven by sympathetic stress, thereby accelerating osteogenesis. Animal studies reveal that infected bone defects exhibit heightened and prolonged sympathetic activity compared to non-infected sites, while GMPP significantly promotes bone regeneration in infected cranial defects in SD rats. This study introduces a novel approach that integrates antibacterial therapy and neuromodulation, highlighting the importance of neural microenvironment remodelling in treating infected bone defects and advancing bone tissue engineering strategies. Schematic illustration of the photosensitive anti-sympathetic GelMA-hMnO₂@PNL@PDA (GMPP) hydrogel facilitating the healing of infected bone defects. • Infected bone defects rats exhibit stronger and more sustained sympathetic activity than non-infected defects. • The GMPP hydrogel exhibits excellent photothermal properties which can effectively eliminate pathogenic bacteria. • The release of propranolol from hydrogel downregulated sympathetic activity and reprogrammed the protein metabolic state. • Propranolol from the GMPP hydrogel countered the inhibitory effects of norepinephrine on angiogenesis and osteogenesis. • GMPP anti-sympathetic hydrogel effectively accelerate the repair of infected cranial bone defects in SD rats.