Enhancing Drug Delivery and Efficacy in Stroke via Supramolecular Nanoparticle Systems

Abstract The pathogenesis of ischemic stroke involves multiple pathological links, such as blood–brain barrier (BBB) disruption, oxidative stress, and neuroinflammation, making comprehensive intervention via a single drug exceedingly difficult. In this study, we constructed a supramolecular coassembly nanoparticles (UA-Gen NPs) composed of Ursolic acid (UA) and Genistein (Gen), which self-assemble into a stable supramolecular structure driven by intermolecular hydrogen bonding and π-π stacking. This nanoplatform not only significantly improved drug hydrophilicity but also achieved a transformation from simple physical mixing to structural integration. In vitro profiles revealed a distinct pH-responsive and sequential release pattern of the system (“fast-Gen/slow-UA”). Pharmacokinetic studies further demonstrated that this coassembly significantly prolonged blood circulation and synchronized the fates of the two drugs in vivo. In a mouse middle cerebral artery occlusion (MCAO) model, UA-Gen NPs exhibited superior efficacy in alleviating BBB leakage, reducing infarct volume, and improving neurobehavioral outcomes compared to their physical mixture. Serological analyses confirmed its regulation of oxidative stress and systemic inflammation, yielding optimal neuroprotection. At the protein expression level, the nanotherapy significantly inhibited Keap1, upregulated Nrf2, and restored Occludin expression. Altogether, by utilizing drug molecules themselves as structural building blocks, this study engineered a supramolecular nanotherapeutic agent featuring microenvironment-responsive release behavior and sequential drug delivery. This work provides a feasible research strategy to overcome the challenges of combination therapy in complex diseases.