Recent Advances in Mitochondria-Targeted Delivery Strategies for Ischemic Stroke Therapy

Ischemic stroke remains a leading cause of death and disability, and mitochondrial dysfunction links bioenergetic failure, oxidative stress, neuroinflammation, blood-brain barrier (BBB) injury, and cell death. Despite extensive preclinical neuroprotection research, translation has often failed because candidate interventions show inadequate brain exposure and mitochondrial target engagement, are tested under pretreatment or simplified experimental conditions, emphasize short-term infarct reduction rather than durable functional recovery, and are difficult to integrate with time-critical reperfusion care. This Review analyzes mitochondria-targeted delivery as a sequential cascade spanning systemic stability, BBB or nose-to-brain entry, lesion and cell selection, endosomal escape, mitochondrial access, and functional rescue. We compare brain-targeted, intranasal, biomimetic, and organelle-transplantation platforms; place recent examples alongside established mitochondria-targeted antioxidant and mitochondrial-transfer literature; and distinguish localization evidence from causal mitochondrial recovery. The most tractable next steps are a standardized, disease-relevant validation framework and simplified delivery designs compatible with acute stroke workflows. Translational success will require integrated systems that address the complete sequential delivery cascade with the minimum necessary complexity, reproducible manufacturing, clinically relevant treatment windows, and long-term functional and safety endpoints.