Beyond Recanalization: Neurovascular Unit Protection and Precision Adjunctive Therapy for Ischemic Stroke in the Reperfusion Era

Intravenous thrombolysis and endovascular thrombectomy (EVT) have increased large-vessel recanalization in acute ischemic stroke, yet macrovascular reopening does not ensure tissue reperfusion or functional recovery. Microvascular no-reflow, blood–brain barrier failure, oxidative injury, thromboinflammation, edema, and hemorrhagic transformation sustain a recanalization-to-recovery gap. Classical neuroprotection failed because of mismatches in models, timing, brain exposure, patient selection, and endpoints, and because ischemic injury was reduced to a single neuronal pathway. Cerebroprotection in the reperfusion era should target the neurovascular unit: delaying penumbral collapse before recanalization, limiting oxidative and vascular injury during thrombectomy, and restoring microcirculatory and barrier function afterwards. Recent trials show a differentiated landscape. ESCAPE-NEXT and RODIN were neutral; TASTE-2 suggested a borderline overall effect and imaging-defined heterogeneity for edaravone dexborneol; BAST supported potential benefit from butylphthalide; and the positive EMPHASIS trial contrasted with neutral EVT-specific MIST-A findings for minocycline. We organize mechanisms and interventions along the macrovascular recanalization–tissue reperfusion–neurovascular-unit preservation–functional recovery continuum, stratify evidence across pharmacological, physiological, delivery, natural-product, and cell/extracellular-vesicle strategies, and propose a precision framework integrating tissue and target windows, reperfusion status, and measurable treatment response. Next-generation trials should combine target engagement, imaging enrichment, prespecified biomarker interactions, and adaptive designs. Current evidence supports redesigning cerebroprotection, not adopting any candidate as a universal adjunct to reperfusion.