Intravenous miR-30c therapy confers dual neurovascular protection and improves long-term recovery after ischemic stroke.

Ischemia-reperfusion (I/R) injury is a major barrier to effective reperfusion therapy in acute ischemic stroke. Secondary microvascular thrombosis and neuronal endoplasmic reticulum (ER) stress are major contributors to poor outcomes, yet therapeutic strategies that simultaneously target both processes remain limited. Here, we investigated the efficacy of an intravenously administered PEGylated liposome-encapsulated miR-30c mimic in a transient middle cerebral artery occlusion (MCAO) mouse model. Endogenous miR-30c was highly expressed in cortical and hippocampal neurons under physiological conditions but was markedly downregulated after ischemia. Post-stroke intravenous delivery restored brain miR-30c levels, reduced infarct volume, and improved neurological function across age and sex groups. Therapeutic benefit was observed within a clinically relevant 3-4.5 h treatment window and was sustained for up to 35 days post-stroke. Mechanistically, miR-30c suppressed endothelial PAI-1, thereby attenuating intravascular fibrin and platelet deposition and preserving microvascular patency, while concurrently attenuating neuronal ER stress and mitochondrial apoptotic signaling to reduce neuronal apoptosis. Together, these findings identify miR-30c as a dual-action therapeutic that confers neurovascular protection and promotes long-term functional recovery after ischemic stroke. Targeting both vascular and neuronal injury pathways may represent a promising strategy to enhance the efficacy of reperfusion therapies in patients with acute ischemic stroke.