A mild photothermal-mediated neuroimmunomodulatory composite hydrogel reverses the inflammatory osteoclast precursor phenotype to promote osteoporotic bone defect healing.

The peripheral sensory nervous system plays a crucial role in the repair of bone injuries. However, the excessive accumulation of oxidative stress and the inflammatory microenvironment lead to insufficient regeneration or dysfunction of sensory nerves, which is closely related to the impaired healing of osteoporotic bone defects (OBD). Therefore, specifically inducing sensory innervation and enhancing its regulatory function on the bone microenvironment has emerged as a highly promising therapeutic strategy. In this study, we developed a multifunctional composite hydrogel (MgAl-LDH@N/GP) by integrating nerve growth factor (NGF)-loaded MgAl-LDH nanosheets into gelatin methacrylamide (GelMA)/polydopamine (PDA) system. This hydrogel facilitates the sustained release of NGF at the bone defect site, which promotes sensory nerve growth. Furthermore, it leverages mild photothermal therapy (mPTT) to activate the transient receptor potential vanilloid 1 (TRPV1) cation channels, thereby enhancing the secretion of the neuropeptide Substance P (SP). This combined therapy significantly reduces the proportion of inflammatory osteoclast precursors (iOCPs) at the defect site, thereby reshaping the local immune response to facilitate bone healing. Both in vitro and in vivo experiments demonstrate that the MgAl-LDH@N/GP hydrogel exhibits excellent biocompatibility. Furthermore, it effectively promotes sensory nerve growth, reverses the iOCP phenotype, and drives robust angiogenesis-osteogenesis coupling. Through this neuro-immune modulation, the system significantly accelerates high-quality bone regeneration.