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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. In vitro and in vivo studies showed that cRGD-Exo@Mn₃O₄ exhibited stronger accumulation in ischemic areas compared to unmodified controls. This nanosystem effectively reduced oxidative stress and neuroinflammation, leading to smaller infarct volumes, alleviated brain edema, and improved neurological function in MCAO/R mice. Mechanistically, transcriptome analysis indicated that its therapeutic effects are associated with regulation of inflammation- and cell death-related pathways, including suppression 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 ability.
References:
DOI:10.1016/j.bioactmat.2026.05.016
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