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May 16, 2026Open Access

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

Puntos clave

The aim is to evaluate engineered Akkermansia muciniphila extracellular vesicles for targeted delivery of miR-21-5p to address postmenopausal osteoporosis.
Developed bone-targeting Akkermansia muciniphila-derived extracellular vesicles (BT-AKK-EVs) with a peptide SDSSD.
Conducted miRNA sequencing to identify miR-21-5p as effective in osteogenic differentiation.
Administered BT-AKK-EVs systemically in ovariectomized mice to assess bone loss alleviation.
BT-AKK-EVs significantly increased bone tissue accumulation of miR-21-5p, promoting osteogenic differentiation.
The treatment group showed significant reduction in bone loss compared to the control group.
Compared to baseline, treatment enhanced the PI3K-AKT pathway activity, confirming its role in the therapeutic effect.

Resumen

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.

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