Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticle-derived multifunctional nanotherapies for
ischemic stroke, which are engineered from a pharmacologically active
oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (
Tempol) and a
hydrogen-peroxide-eliminating moiety of
phenylboronic acid pinacol ester (PBAP) on β-
cyclodextrin. Of note, combined functional moieties of
Tempol and PBAP on β-
cyclodextrin contribute to antioxidative and anti-inflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced
oxygen-
glucose deprivation-induced overproduction of oxidative mediators, increased
antioxidant enzyme expression, and suppressed microglial-mediated
inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with
middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of
stroke. Therapeutically, TPCD NPs significantly decreased
infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, anti-inflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a
reactive oxygen species labile nanovehicle to efficiently load and triggerably release an
inflammation-resolving
peptide Ac2-26, giving rise to an
inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional
inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted
therapies for
stroke and other
inflammation-associated
cerebrovascular diseases.