Mild photothermal-mediated neuroimmunomodulatory composite hydrogel ameliorates bone healing microenvironment for enhanced osteoporotic bone defect regeneration

The treatment of osteoporotic bone defects represents a substantial clinical challenge in contemporary orthopedics due to the abnormal accumulation of reactive oxygen species (ROS) and elevated inflammatory levels. Despite advances in bone graft materials for enhancing bone regeneration, developing an ideal therapeutic strategy capable of orchestrating the multidimensional biological processes underlying bone healing, such as immunomodulation, angiogenesis, osteogenesis and innervation, remains a formidable challenge in orthopedic biomaterial design. In our study, a multifunctional composite hydrogel (Ce@Mo/GC) was developed through the incorporation of CeO 2 @Mo 2 Ti 2 C 3 MXene (Ce@Mo) heterojunction structures into gelatin methacryloyl (GelMA)/carboxymethyl chitosan (CMCS) for optimizing the osteogenic microenvironment in osteoporotic bone defects. The Ce@Mo system integrates multiple enzyme-like activities with NIR-responsive photothermal effects, enabling effective ROS scavenging at defect sites through mild hyperthermia-enhanced Ce 3+ /Ce 4+ valence transitions in CeO 2 , while promoting macrophage polarization to M2 phenotype to modulate immune responses. Additionally, localized administration of Ce@Mo/GC can promote bone healing by inducing neurogenesis in the defect site and triggering the spatiotemporal release of neuropeptides through mild photothermal stimulation. Both in vitro and in vivo experiments demonstrated that the Ce@Mo/GC hydrogel exhibits excellent biocompatibility while effectively modulating inflammatory responses, promoting osteogenic differentiation, angiogenesis and achieving nerve immune regulation to promote bone healing.