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Published on: August 23, 2024
Engineered Akkermansia muciniphila extracellular vesicles for targeted delivery of miR-21-5p alleviate postmenopausal
Ning Ji1,2,3, Jing Zhao1,2,3, Yingrui Mao4
1Institute of Translational Medicine, Organoid Research Center, Shanghai University, Shanghai, 200444, China.
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.
Insights
Engineered bacterial extracellular vesicles (BEVs) from Akkermansia muciniphila target bone, delivering miR-21-5p to treat osteoporosis by promoting bone formation and inhibiting bone loss. This gut-bone axis approach offers a novel therapeutic strategy.
Area of Science:
- Biomaterials Science
- Molecular Biology
- Translational Medicine
Background:
- Osteoporosis (OP) is a metabolic bone disease characterized by low bone density and impaired structure.
- Current OP treatments face limitations due to non-specific targeting and toxicity.
- The gut-bone axis offers a novel therapeutic avenue, leading to the development of engineered bacterial extracellular vesicles (BEVs) from probiotic Akkermansia muciniphila (AKK).
Purpose of the Study:
- To develop an engineered bacterial extracellular vesicle (BEV) system for targeted osteoporosis therapy.
- To elucidate the molecular mechanism underlying the therapeutic effects of BEVs in the context of the gut-bone axis.
- To evaluate the efficacy of engineered BEVs in an in vivo osteoporosis model.
Main Methods:
- Engineered bacterial extracellular vesicles (BEVs) from Akkermansia muciniphila (AKK) were developed and decorated with a bone-targeting peptide (BT-AKK-EVs).
- MiRNA sequencing and functional assays were performed to identify key effector molecules.
- The PI3K-AKT signaling pathway was investigated for its role in osteogenesis and osteoclastogenesis.
- Therapeutic efficacy was assessed in ovariectomized mice.
Main Results:
- Engineered BEVs (BT-AKK-EVs) successfully targeted bone tissues.
- MiR-21-5p was identified as a crucial molecule enriched in AKK-EVs.
- BT-AKK-EVs promoted osteogenic differentiation and inhibited osteoclastogenesis via the PI3K-AKT pathway.
- Systemic administration of BT-AKK-EVs significantly alleviated bone loss in vivo.
Conclusions:
- Engineered probiotic BEVs represent a safe and effective platform for targeted bone therapy.
- Vesicle-packaged microRNAs (miRNAs) mediate gut-bone communication, offering a novel therapeutic mechanism.
- This approach provides a transformative strategy for treating metabolic bone disorders like osteoporosis.
