Epoxomicin-functionalized thermosensitive hydrogel rescues bone defects in osteoporosis by the NF-κB signaling pathway.

To address the clinical challenge of difficult bone defect healing in osteoporosis patients, this study developed a functional delivery system based on a thermosensitive hydrogel loaded with epoxomicin (CS-βGP@10Epoxomicin). This system possesses injectability and body-temperature-triggered in situ gelation properties, overcoming the poor targeting and potential complications associated with systemic drug administration, while achieving dual anti-inflammatory and osteoclast-inhibitory effects within the local bone defect microenvironment. In vitro experiments confirmed its ability to significantly reduce the expression of inflammatory cytokines and osteoclast-related factors. In an ovariectomized (OVX) mouse femoral defect model, local application of this hydrogel significantly increased bone mineral density (BMD) at the defect site by 53.47% compared to the OVX group and downregulated the expression of the inflammatory cytokine interleukin-1 beta (IL-1β) by 27.37%. The system maintained favorable biocompatibility while effectively inhibiting the activation of the nuclear factor kappa-B (NF-κB) signaling pathway, alleviating inflammatory responses and suppressing osteoclast differentiation. Transcriptomic analysis of a public dataset further supported the central role of the NF-κB pathway in the pathological microenvironment of osteoporosis. In summary, this study establishes an intelligent localized delivery strategy that integrates targetability, safety and therapeutic efficacy, providing a potential solution for the local treatment of osteoporotic bone defects.