Blood–brain barrier permeating dendrimers for alleviation of cerebral ischemia–reperfusion injury

Ischemia–reperfusion injury (IRI) is a major contributor to incomplete neurological recovery after ischemic stroke, particularly after reperfusion therapies such as thrombolysis or mechanical thrombectomy. Reperfusion can trigger excessive generation of reactive oxygen and nitrogen species (RONS) and amplify inflammatory cell recruitment, thereby driving secondary brain injury. Although numerous neuroprotective and immunomodulatory agents have been explored for mitigating IRI, their brain penetration capacity and therapeutic efficacy are limited in part by the blood–brain barrier (BBB), which restricts drug accumulation within the brain parenchyma. To overcome this challenge, we developed a RONS-scavenging dendrimer, G4-PB-PEG, with prolonged systemic circulation and a RONS-responsive PEG shell. In the ischemic microenvironment with excessive RONS, stimulus-responsive PEG deshielding facilitates BBB penetration and lesion-selective accumulation, thereby enabling efficient scavenging of pathological RONS. In a mouse model of transient middle cerebral artery occlusion, intravenously administered G4-PB-PEG exhibited preferential accumulation at the cerebral lesion. By effectively scavenging RONS and attenuating neuroinflammatory responses, G4-PB-PEG significantly decreased infarct volume and the levels of neuroinflammation markers. Neurological outcomes also improved markedly, as quantified using the modified neurological severity score. These results indicate that G4-PB-PEG effectively alleviates cerebral IRI by facilitating BBB penetration and lesion-selective accumulation, with potent neuroprotective effects. Therefore, G4-PB-PEG warrants further evaluation for clinical translation.