Sphinganine (d17:0)-enriched outer membrane vesicles from Parabacteroides goldsteinii alleviate obesity via modulating mitochondrial dynamics

Obesity, a global crisis linking metabolic syndrome and inflammation, remains inadequately addressed. In this study, we found that outer membrane vesicles derived from Parabacteroides goldsteinii (PGOMV) were more effective than live or pasteurized bacteria in alleviating high‑fat diet (HFD)‑induced obesity. Multi-omics analysis indicates that PGOMV regulates metabolic homeostasis by modulating the levels of key metabolites such as 3-hydroxybutyric acid and by modulating the gut microbiota. Its key bioactive component, sphinganine (d17:0, SA), directly binds to the mitochondrial fission proteins DRP1 and MFF, inhibiting excessive fission, thereby alleviating oxidative stress and inflammation, and disrupting the lipid–inflammation–oxidative damage vicious cycle. Based on this, we engineered an orally deliverable SA‑enriched system, PGOMV@SA. In models of HFD-induced obesity and obesity-comorbid psoriasis, PGOMV@SA simultaneously ameliorated metabolic disorders and inflammatory skin lesions. This study demonstrates that SA delivered via bacterial vesicles exhibits dual metabolic and immunomodulatory functions, providing a novel nanotherapeutic strategy for obesity‑associated inflammatory diseases. Parabacteroides goldsteinii -derived outer membrane vesicles (PGOMVs) are enriched with active components such as sphinganine (d17:0, SA), effectively alleviating obesity and metabolic inflammation. To further enhance its therapeutic efficacy, we engineered PGOMV@SA, a nanotherapeutic targeting the gut–liver axis. Its cargo, SA, directly binds to DRP1 and MFF, thereby blocking pathological mitochondrial fission and mitigating metabolic inflammation, providing a novel microbiome-inspired intervention strategy for obesity and related inflammatory diseases.