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

多功能离子/药物共递送纳米复合水凝胶调控神经成骨微环境，促进骨质疏松性骨整合

Shengyang Jin, Ismat Ullah, Zhaowei Chen, Yuwei Ge, Tao Feng, Yan Yang, Qi Yan, Jinning Wang, Dawei Song, Zicheng Deng, Zhenfei Huang, Wei Cui, Hui Sun, Junjie Niu, Liang Yang (2026) Multifunctional ions/drugs co-delivering nanocomposite hydrogel orchestrates neuro-osteogenic microenvironment for boosting osteoporotic osseointegration. J Nanobiotechnology (IF: 12.6) 1 区

Abstract

With population aging, the incidence of osteoporosis continuously elevates worldwide, resulting in increased fracture risks and clinical demand for orthopedic fixation. However, under osteoporotic conditions, the stability and longevity of implants are severely compromised by the pathological microenvironment, thus developing effective therapeutic interventions to achieve successful osteoporotic osseointegration remains a critical challenge in the regenerative medicine field. Herein, the parathyroid hormone (PTH) is encapsulated in Sr2+/Zn2+ 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.© 2026. The Author(s).

随着人口老龄化，骨质疏松症的发病率在全球范围内持续上升，导致骨折风险增加，对骨科内固定的临床需求也随之增长。然而，在骨质疏松状态下，病理微环境会严重损害植入物的稳定性和使用寿命，因此，开发有效的治疗干预措施以实现成功的骨质疏松性骨整合仍然是再生医学领域的一项关键挑战。本文中，甲状旁腺激素（PTH）被封装在Sr2+/Zn2+共掺杂的介孔二氧化硅纳米颗粒（SrZn-MSNs）中，合成P@SrZn-MSNs，然后将其掺入含有降钙素基因相关肽（CGRP）的明胶甲基丙烯酸酯（GelMA）中，以实现生物活性离子/药物的共递送。所制备的Gel/P@SrZn-MSNs/G纳米复合水凝胶具有优异的注射性和光敏性、三维互连多孔结构、持久降解性以及可控释放Si/Sr/Zn离子、CGRP和PTH等分子的特性。这些优异的性能赋予Gel/P@SrZn-MSNs/G卓越的生物多功能性，不仅能直接促进背根神经节（DRG）感觉神经元和骨髓间充质干细胞（BMSCs）的功能，还能调控DRG/BMSCs之间的互利相互作用，进一步刺激神经发生/成骨作用。具体而言，Gel/P@SrZn-MSNs/G主要通过增加BMSCs中NGF和BDNF的表达来刺激轴突生长和DRG神经元的活化，进而上调DRG神经元中Sema3A的表达，从而促进神经诱导的成骨作用。体内实验结果进一步证实，当将Gel/P@SrZn-MSNs/G应用于卵巢切除（OVX）大鼠股骨髁缺损部位时，可有效且及时地诱导种植体周围神经支配和骨形成。这些结果凸显了高效的离子/药物共递送系统赋予Gel/P@SrZn-MSNs/G协同生物效应，从而构建所需的神经成骨微环境，促进骨质疏松性骨整合，这可能为骨质疏松性骨愈合提供新的治疗策略。© 2026. 作者。

Links

http://www.ncbi.nlm.nih.gov/pubmed/41981450
http://dx.doi.org/10.1186/s12951-026-04398-y

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