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

Published: 25 December 2025| Version 1 | DOI: 10.17632/mk7p2ryv5p.1
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Description

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.

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Categories

Microbiology, Health Sciences, Orthopedics, Cell Biology, Biologicals, Extracellular Vesicle

Funders

  • National Key Research and Development Program of China
    Grant ID: 2024YFC2510400
  • Shanghai Committee of Science and Technology Laboratory Animal Research Project
    Grant ID: 23141900600
  • Regional Innovation Development Joint Fund of National Natural Science Foundation of China
    Grant ID: U24A20376
  • Jiangsu Province Natural Science Foundation Project
    Grant ID: BK20241808
  • Fujian Province Natural Science Foundation Project
    Grant ID: 2024J01221
  • Jiangsu Province Youth Science and Technology Talent Support Project
    Grant ID: JSTJ-2024-097
  • Zhejiang Provincial Natural Science Foundation of China under Grant
    Grant ID: LMS25H060006

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