Ergosterol-loaded brain-targeted liposomes attenuate stroke via gut microbiota-metabolite-brain axis modulation

Ischemic stroke lacks effective neurorestorative options. We developed a lactoferrin-guided, long-circulating liposomal formulation of ergosterol (Erg) to enhance brain delivery and probed its mechanism along the gut-brain axis. The liposomes exhibited oxidative microenvironment-accelerated destabilization and drug release under H₂O₂ exposure, thereby enhancing brain accumulation and therapeutic efficacy. In rodent models, Erg liposomes preferentially accumulated in the brain, reduced infarct burden, suppressed neuroinflammation and apoptosis, and improved neurological scores and motor function, which suggests robust functional recovery. Multi-omics correlation analysis indicates that Erg treatment reversed gut dysbiosis and elevated medium-chain fatty acids (e.g., heptanoate), which was spatiotemporally associated with PI3K/AKT/mTOR pathway activation in the brain. Together, these findings support a mechanism whereby Erg promotes recovery via coordinated brain targeting and gut-brain axis modulation, linking microbial metabolite remodeling to pro-survival signaling and highlighting a mechanistically informed strategy for post-stroke neuroprotection.