pH‐Sensitive, Cerebral Vasculature‐Targeting Hydroxyethyl Starch Functionalized Nanoparticles for Improved Angiogenesis and Neurological Function Recovery in Ischemic Stroke

Abstract Angiogenesis, an essential restorative process following ischemia, is a promising therapeutic approach to improve neurological deficits. However, overcoming the blood–brain barrier (BBB) and effective drug enrichment are challenges for conventional drug delivery methods, which has limited the development of treatment strategies. Herein, a dual‐targeted therapeutic strategy is reported to enable pH‐sensitive drug release and allow cerebral ischemia targeting to improve stroke therapeutic efficacy. Targeted delivery is achieved by surface conjugation of Pro‐His‐Ser‐Arg‐Asn (PHSRN) peptides, which binds to integrin α 5 β 1 enriched in the cerebral vasculature of ischemic tissue. Subsequently, smoothened agonist (SAG), an activator of sonic hedgehog (Shh) signaling, is coupled to PHSRN‐HES by pH‐dependent electrostatic adsorption. SAG@PHSRN‐HES nanoparticles can sensitively release more SAG in the acidic environment of ischemic brain tissue. More importantly, SAG@PHSRN‐HES exerts the synergistic mechanisms of PHSRN and SAG to promote angiogenesis and BBB integrity, thus improving neuroplasticity and neurological function recovery. This study proposes a new approach to improve the delivery of medications in the ischemic brain. Dual‐targeted therapeutic strategies have excellent potential to treat patients suffering from cerebral infarction.