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Background <p>Osteoporosis (OP) is a common metabolic bone disease marked by decreased bone density and impaired bone structure. Conventional therapeutic strategies for OP are restricted by their non-specific targeting and long-term toxicity. Leveraging the gut-bone axis, we developed an engineered bacterial extracellular vesicles (BEVs) delivery system derived from probiotic <i>Akkermansia muciniphila</i> (AKK).</p> Results <p>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 promote 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.</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Ning Ji,
  • Jing Zhao,
  • Yingrui Mao,
  • Jin Zhang,
  • Xiao Chen,
  • Yan Hu,
  • Hao Zhang,
  • Yingying Jing,
  • Yingying Jiang,
  • Xiaoxiang Ren,
  • Xiuhui Wang,
  • Chongru He,
  • Ke Xu,
  • Han Liu,
  • Jiacan Su

摘要

Background

Osteoporosis (OP) is a common metabolic bone disease marked by decreased bone density and impaired bone structure. Conventional therapeutic strategies for OP are restricted by their non-specific targeting and long-term toxicity. Leveraging the gut-bone axis, we developed an engineered bacterial extracellular vesicles (BEVs) delivery system derived from probiotic Akkermansia muciniphila (AKK).

Results

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 promote 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.

Conclusions

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.

Graphical Abstract