Multifunctional ions/drugs co-delivering nanocomposite hydrogel orchestrates neuro-osteogenic microenvironment for boosting osteoporotic osseointegration

co-doped mesoporous silica nanoparticles (SrZn-MSNs) to synthesize P@SrZn-MSNs, which are then incorporated into gelatin methacrylate (GelMA) containing calcitonin gene related peptide (CGRP) for realizing bioactive ions/drugs co-delivery. The obtained Gel/P@SrZn-MSNs/G nanocomposite hydrogels are characterized by excellent injectability and photosensitivity, 3D interconnected porous architecture, durable degradation and concurrent releasing of Si/Sr/Zn ions, CGRP and PTH controlled within proper doses. These favorable properties endow Gel/P@SrZn-MSNs/G with superior biological multifunctionality that not only promotes functionality of DRG sensory neurons and BMSCs directly, but also manipulates mutually beneficial interactions of DRG/BMSCs to further stimulate neurogenesis/osteogenesis. Specifically, Gel/P@SrZn-MSNs/G mainly increases NGF and BDNF expressions in BMSCs to stimulate axonal outgrowth and activation of DRG neurons, and in turn, the up-regulation of Sema3A in DRG neurons could be responsible for the neuro-inductive osteogenesis. Consistently, the in vivo outcomes further validate the potent and timely peri-implant innervation and bone formation induced by Gel/P@SrZn-MSNs/G when applied to femoral condyle defects of OVX rats. These results highlight the efficient ions/drugs co-delivery system renders Gel/P@SrZn-MSNs/G exerting synergy bioeffects to orchestrate desired neuro-osteogenic niches for boosting osteoporotic osseointegration, thus may inspiring new therapeutic strategies for osteoporotic bone healing.