Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.

血糖波动导致 2 型糖尿病 （T2DM） 患者的骨缺损修复不良。安全有效地改善由血糖波动引起的骨再生障碍的策略仍然是一个挑战。中性鞘磷脂酶 2 （Smpd3） 在 T2DM 患者的颌骨来源骨髓间充质干细胞 （BMSC） 中下调。在这里，我们研究了 Smpd3 对 BMSCs 成骨分化的影响，并基于苯硼酸基聚乙烯醇交联剂的葡萄糖反应性和明胶纳米颗粒的蛋白酶降解性，利用过表达 Smpd3 的干细胞外泌体作为主要处理。Smpd3 过表达干细胞衍生的外泌体 （Exos-Smpd3） 和纳米银离子 （Ns） 的联合负载构建水凝胶递送系统 （Exos-Smpd3@Ns） 促进了 BMSCs 在葡萄糖波动环境中的成骨和分化，在葡萄糖波动环境中促进了 BMSCs 的异位成骨和糖尿病犬在体外的颚骨再生。从机制上讲，Smpd3 通过激活颚骨中的自噬并抑制血糖波动引起的巨噬细胞极化和氧化应激来促进颚骨衍生的 BMSCs 的成骨和分化。这些结果揭示了 Smpd3 和 Smpd3 过表达外泌体递送系统在血糖波动下促进 BMSC 功能和骨再生的作用和机制，为治疗 T2DM 患者骨缺损提供了理论依据和候选方法。