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.

© 2024. The Author(s).

血糖波动会导致2型糖尿病（T2DM）患者骨骼修复不良。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。中性鞘氨磷脂裂解酶2（Smpd3）在T2DM患者的颌骨来源的骨髓间充质干细胞（BMSCs）中的表达下调。在这里，我们研究了Smpd3对BMSC成骨分化的效应，并基于苯硼酸基聚乙烯醇交联剂的葡萄糖响应性和明胶纳米粒子的蛋白酶降解性，利用过表达Smpd3的干细胞分泌的外泌体作为主要治疗方法。将过表达Smpd3的干细胞衍生的外泌体（Exos-Smpd3）和纳米银离子（Ns）联合负载以构建水凝胶递送系统（Exos-Smpd3@Ns），在血糖波动环境中促进了BMSCs的成骨作用和分化，异位成骨以及糖尿病狗颌骨再生。机制上，Smpd3通过激活颌骨中的自噬、抑制由血糖波动引起的巨噬细胞极化和氧化应激来促进来自颌骨的BMSC的成骨作用和分化。这些结果揭示了Smpd3及其过表达外泌体递送系统在促进BMSC功能和血糖波动下的骨再生中的角色与机制，为T2DM患者的骨缺陷治疗提供了理论基础和候选方法。