Beyond Blood-Brain Barrier Crossing in Reperfusion-Era Ischemic Stroke: Interface-Matched Active-Entity Delivery and Translational Product Design

Reperfusion therapy has transformed acute ischemic stroke care, yet large-vessel recanalization does not ensure capillary reperfusion, preservation of the blood-brain barrier and neurovascular unit (BBB/NVU), or durable neurological recovery. Nanomedicine is still commonly judged by BBB crossing or ischemic-hemisphere accumulation, although vascular access, tissue viability, transport phenotype, thromboinflammation, and standard treatment change rapidly during the lifetime of a formulation. This narrative review proposes a conceptual framework that matches the reperfusion state and pathological interface to the compartment in which the therapeutically active entity must act. The framework is intended to organize preclinical evidence and generate testable translational hypotheses; it has not yet been clinically validated. Persistent occlusion may favor intravascular targets, whereas recanalization with no-reflow creates a distinct microvascular delivery problem. Early reperfusion injury may prioritize BBB/NVU stabilization, while later biological contexts may require selective immune, regenerative, or organelle-directed interventions. These contexts may coexist spatially, vary across vascular territories, and shift during treatment; they should therefore not be interpreted as a mandatory chronological sequence. We distinguish BBB crossing, controlled barrier modulation, and BBB/NVU repair as separate therapeutic tasks, and introduce transport attrition as a practical explanation for why sequential targeting, transcytosis, cellular uptake, endosomal escape, and organelle localization can yield little final active-entity exposure despite strong tissue imaging. Recent predominantly preclinical examples illustrate how thrombus-targeted rtPA systems, neutrophil-intercepting particles, NET-degrading polymersomes, lesion-targeted nanoplatforms, and mitochondrial nanomedicines may fit different delivery topologies. Translational credibility requires topology-resolved exposure, target engagement in viable tissue, hemocompatibility under antithrombotic treatment, state-appropriate models, function-linked manufacturing controls, and compatibility with thrombolysis and thrombectomy.