Amelioration of Post‐Stroke Edema and Microcirculatory Dysfunction via Targeted AQP4 Inhibition While Preserving the Glymphatic System

Abstract Cerebral edema and hypoperfusion, hallmark pathologies of both hemorrhagic and ischemic stroke, critically compromise clinical outcomes. Astrocytic aquaporin‐4 (AQP4) not only drives post‐stroke brain edema progression but also maintains the protective clearance function of the glymphatic system. Herein, systemic AQP4 inhibition using TGN‐020 (TGN) paradoxically exacerbates global glymphatic dysfunction despite alleviating cerebral edema and microcirculatory dysfunction following subarachnoid hemorrhage (SAH). To overcome this therapeutic dilemma, an angiopep‐2‐functionalized lipid nanoparticle (A‐LNP) platform enabling lesion‐targeted TGN delivery is engineered. This system reverses the detrimental effects of TGN on the post‐SAH glymphatic system while enhancing the therapeutic benefits of TGN in mitigating cerebral edema and microcirculatory dysfunction. Remarkably, TGN demonstrates multimodal efficacy in ischemic stroke by mitigating the no‐reflow phenomenon, alleviating blood‐brain barrier disruption, and suppressing neuroinflammation. The A‐LNP system retains the protective effects of TGN without compromising global glymphatic function, leading to enhanced therapeutic efficacy. These findings confirm the feasibility of using functional nanoparticles to enhance the protective effects of AQP4 inhibition while minimizing adverse effects on the glymphatic system, offering a promising therapeutic strategy for both stroke subtypes.