Engineered Akkermansia muciniphila extracellular vesicles for targeted delivery of miR-21-5p alleviate postmenopausal osteoporosis via PI3K-AKT pathway

Osteoporosis (OP) is a common metabolic bone disease marked by decreased bone density and impaired bone structure. Conventional therapeutic strategies for OP restricted due to their non-specific targeting and long-term toxicity. Leveraging the gut-bone axis, we developed an engineered bacterial extracellular vesicle (BEV) delivery system derived from probiotic Akkermansia muciniphila (AKK). These BEVs were engineered with a bone-targeting peptide (SDSSD) to generate BT-AKK-EVs. Through miRNA sequencing and functional experiments, we identified miR-21-5p as a pivotal effector molecule enriched within AKK-EVs. Mechanistically, BT-AKK-EVs delivered miR-21-5p to promoting osteogenic differentiation while simultaneously inhibiting osteoclastogenesis via activation of the PI3K-AKT signaling pathway. Systemic administration of BT-AKK-EVs in ovariectomized mice resulted in their robust accumulation in bone tissues, significantly alleviating bone loss. This study establishes engineered probiotic BEVs as a safe and efficient platform for targeted bone therapy and elucidates a concrete molecular mechanism of gut-bone communication through vesicle-packaged miRNA, offering a transformative strategy for treating metabolic bone disorders.

骨质疏松症（Osteoporosis, OP）是一种常见的代谢性骨病，以骨密度降低与骨结构受损为典型特征。其常规治疗策略因靶向特异性不足及长期毒性问题而应用受限。本研究利用肠-骨轴（gut-bone axis），开发了一种源自益生菌黏蛋白阿克曼菌（Akkermansia muciniphila, AKK）的工程化细菌细胞外囊泡（bacterial extracellular vesicle, BEV）递送系统。研究人员通过修饰骨靶向肽（SDSSD）对这类BEV进行工程化改造，成功构建得到BT-AKK-EVs。通过微小RNA（microRNA, miRNA）测序与功能实验，我们鉴定出miR-21-5p是富集于AKK-EVs中的关键效应分子。机制层面研究表明，BT-AKK-EVs通过递送miR-21-5p激活PI3K-AKT信号通路，可同时促进成骨分化并抑制破骨细胞生成。在去卵巢小鼠模型中对BT-AKK-EVs进行全身给药后，其可在骨组织中大量富集，显著减轻骨丢失。本研究证实，工程化益生菌来源的BEV是一种安全高效的靶向骨治疗平台，并阐明了通过囊泡包裹微小RNA实现肠-骨信号交流的具体分子机制，为代谢性骨病的治疗提供了革新性策略。