Astrocyte-targeted nanovesicle delivery of resveratrol activates SIRT1 to suppress neuroinflammation and restore neural homeostasis in epilepsy

Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes. These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation. Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood–brain barrier (BBB) permeability and poor astrocytic specificity. A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol (RN@RTA) was developed to regulate astrocyte-mediated inflammation by activating SIRT1 and suppressing the MAPK/NF-κB axis. Using <em>in vitro</em> BBB models, primary astrocytes, and a pilocarpine-induced chronic epilepsy mouse model, we evaluated the capacity of RN@RTA to cross the BBB, inhibit inflammatory signaling, and reduce seizure activity. Mechanistic assays included immunoprecipitation of NF-κB complexes, cytokine quantification, RNA sequencing, and histopathological assessments of glial and synaptic markers. RN@RTA achieved 82% uptake by hippocampal astrocytes and significantly reduced <em>Il6</em>, <em>Tnf-α</em>, and <em>Nlrp3</em> expression. SIRT1 activation disrupted the NF-κB p65/p300 complex, leading to transcriptional repression of inflammatory genes and enhancement of autophagy. <em>In vivo</em>, seizure frequency decreased by 67%, synaptic structure was preserved, and astrogliosis was markedly alleviated. The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis, offering a promising molecularly targeted approach for refractory epilepsy.