Enhanced treatment of ischemic stroke by scutellarin loaded Angiopep-2-modified milk exosomes via multiple pathological pathways regulation.

Ischemic stroke is a major cerebrovascular disease with high morbidity and mortality. However, effective treatments remain limited due to the narrow thrombolytic window, ischemia-reperfusion injury, and restricted drug delivery across the blood-brain barrier (BBB). Due to multiple pathological processes including oxidative stress, inflammation, mitochondrial dysfunction, and microglial dysregulation involved in ischemic stroke, it is urgent to develop drug delivery systems capable of crossing the BBB and targeting multiple pathological pathways. Scutellarin (SCU) exhibits neuroprotective effects while its application is constrained by low bioavailability, rapid clearance, and poor stability. This study developed an Angiopep-2 (ANG-2)-modified milk exosome delivery system loaded with SCU (SCU@AMExo) for ischemic stroke therapy. SCU@AMExo improved the bioavailability and stability of SCU, facilitated efficient BBB penetration, and exerted neuroprotective effects by reducing oxidative stress, alleviating mitochondrial dysfunction, inhibiting NLRP3 inflammasome activation, and regulating microglial polarization. In vitro, SCU@AMExo increased the cell viability of PC12 cells with Oxygen-Glucose Deprivation/Reperfusion (OGD/R) injury from 48.1% to 92.9%. In transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mice, SCU@AMExo reduced the cerebral infarct volume from 51.06% to 11.29%, inhibited neuronal apoptosis, and alleviated neurological deficits. These results demonstrate that SCU@AMExo is an effective brain-targeted drug delivery system for ischemic stroke through multi-pathway neuroprotection.