The treatment of ischemic stroke (IS) is seriously limited by insufficient drug accumulation in the ischemic lesions and ongoing secondary damage after ischemia-reperfusion. This paper reports a cRGD-functionalized exosome-based nanoplatform that can boost drug accumulation in ischemic lesions and enhance its antioxidant neuroprotective effects for IS therapy. We functionalized neural stem cell-derived exosomes with cyclic RGD peptides (cRGD) and then loaded Mn₃O₄ nanoparticles to create a hybrid nanosystem (cRGD-Exo@Mn₃O₄). The modified exosomes retained their inherent brain-targeting ability, while the cRGD modification promoted preferential accumulation in ischemic areas, likely through interaction with the highly expressed αvβ3 integrins in the ischemic lesions. The introduced Mn₃O₄ nanoparticles provided strong reactive oxygen species (ROS) scavenging capability, reducing oxidative stress in the ischemic microenvironment. Both in vitro and in vivo studies showed that cRGD-Exo@Mn₃O₄ accumulated more strongly in ischemic areas compared to unmodified controls. This nanosystem effectively alleviated oxidative stress and neuroinflammation, reducing infarct volume, easing brain edema, and improving neurological function in MCAO/R mice. Mechanistically, transcriptome analysis indicated that its therapeutic effects were linked to regulation of inflammation and cell death pathways, including inhibition of the RIPK1/RIPK3/MLKL signaling cascade. Overall, this study presents a rationally designed exosome-based nanoplatform that combines ischemic lesion-targeted accumulation with ROS scavenging capability.

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