A dual-responsive hydrogel enables integrated regulation of the neuro-osseous axis by geniposide and strontium ions for bone defect repair

Thermo/pH-responsive STGF hydrogel enables sequential geniposide/Sr ion delivery for bone repair. • Dual-responsive platform integrating herbal therapeutics and bioactive ions regulates bone repair microenvironment. • Geniposide boosts Schwann cell neurotrophic support via PI3K/Akt/GSK-3β and promotes BDNF secretion. • BDNF-mediated Schwann-osteoblast crosstalk drives neuro-osseous coupling and osteogenic regeneration. • Coordinated inflammation regulation, neurotrophic support, and osteogenesis for multifunctional bone repair. The repair of bone defects is often hindered by excessive inflammation and impaired neurotrophic support. To address these challenges, we developed a thermosensitive and pH-dual-responsive composite hydrogel, Sr-TA NPs-GEN-F127 (STGF), incorporating geniposide (GEN) and strontium-tannic acid nanoparticles (Sr-TA NPs). Upon exposure to the locally acidified microenvironment, STGF responds to environmental acidity and releases GEN and Sr 2+ in a controlled manner. These two components jointly regulate TNF-α/NF-κB signaling, contributing to the attenuation of inflammatory responses and the establishment of a favorable microenvironment for tissue repair. Meanwhile, GEN selectively targets Schwann cells at the defect margins and promotes sustained paracrine secretion of brain-derived neurotrophic factor (BDNF) through activation of the PI3K/Akt/GSK-3β pathway. This multiscale cellular communication contributes to the regulation of the local neuro-osseous axis and acts in spatiotemporal synergy with the direct mineralization-promoting effects of Sr 2+ , thereby promoting the expression of key osteogenic genes, including RUNX2 and ALP. In vivo rat models demonstrated that the STGF hydrogel significantly accelerated mature bone regeneration and promoted defect closure within 28 days. This study reveals an endogenous anti-inflammatory, neural, and osteogenic integrated regulatory mechanism and provides a physiologically relevant intervention strategy for the structural reconstruction of bone defects.