Berberine Liposome Nanoparticles as a Potential Therapeutic Strategy for Managing Ischemic Stroke Through PTGS2 Inhibition

Pyroptosis following cerebral ischemia–reperfusion injury (CIRI) is a key driver of long‐term neuronal damage and poor functional recovery. Microglia, the primary immune cells of the central nervous system (CNS), play a pivotal role in regulating pyroptosis and orchestrating neuroinflammation. In this study, we observed significant upregulation of prostaglandin endoperoxide synthase‐2/cyclooxygenase‐2 (PTGS2/COX‐2) in ischemic stroke patients, as well as in both in vivo and in vitro CIRI models. Knockdown of PTGS2 attenuated pyroptosis in BV2 microglial cells exposed to oxygen‐glucose deprivation/reoxygenation (OGD/R). Using network pharmacology and molecular docking, we identified berberine (BBR) as a specific PTGS2 inhibitor, capable of suppressing its expression. To overcome BBR’s poor aqueous solubility and low bioavailability, we developed a novel nanoliposomal formulation of BBR (BBR‐LNPs). In a murine middle cerebral artery occlusion/reperfusion (MCAO/R) model, BBR‐LNPs markedly alleviated neurological dysfunction and reduced CIRI by regulating PTGS2‐mediated pyroptosis. Collectively, our findings demonstrate that BBR‐LNPs mitigate CIRI by inhibiting PTGS2‐dependent pyroptosis, highlighting their potential as a therapeutic strategy for ischemic stroke.