Abstract
PURPOSE: The pathological mechanisms underlying ischemic stroke are highly complex, with the neuroinflammatory response triggered by cerebral ischemia-reperfusion being a major contributor to secondary brain damage. This response significantly impedes neural tissue regeneration. Despite advancements in treatment, current anti-inflammatory strategies remain suboptimal in terms of safety and efficacy. This study aimed to develop an all-natural nanomedicine delivery system for the transnasal administration of puerarin, combined with the endogenous anti-inflammatory peptide Ac2-26, to enhance neuroprotection against ischemic stroke through a synergistic anti-inflammatory approach. METHODS: In this study, collagen nanoparticles (PueNps) loaded with puerarin were synthesized, followed by the preparation of a chitosan hydrogel. The PueNps and Ac2-26 were co-encapsulated within the hydrogel, resulting in the formation of the PueNps&Ac2-26 gel formulation. The physicochemical properties of this formulation, as well as its biodistribution and anti-ischemic efficacy in the MCAO rat brain, were evaluated. RESULTS: In this formulation system, the bioavailability of puerarin and Ac2-26 was enhanced, exhibiting sustained-release properties, which enabled efficient brain-targeted delivery. It effectively alleviated neurological impairment in MCAO rats, reduced the volume of cerebral infarction, and decreased brain water content. Additionally, the PueNps&Ac2-26 gel significantly inhibited neuroinflammation in rats and alleviated oxidative stress. CONCLUSION: The PueNps&Ac2-26 gel is a purely natural and efficient formulation system, offering a promising approach for the clinical treatment of ischemic stroke in the future.