Multi-target neuroprotective mechanisms of epigallocatechin-3-gallate (EGCG) in stroke: from molecular pathways to nanomedicine delivery and clinical translation

Abstract

Stroke ranks among the leading global causes of mortality and permanent disability. Its secondary brain injury arises from multiple interrelated pathological cascades, including oxidative stress, neuroinflammation, disrupted autophagy-apoptosis balance, excitotoxicity, iron dyshomeostasis, and blood–brain barrier (BBB) dysfunction. Although intravenous thrombolysis and mechanical thrombectomy have greatly improved the efficacy of acute reperfusion therapy, effective neuroprotective regimens for secondary brain injury remain scarce. Epigallocatechin-3-gallate (EGCG), the most abundant and biologically potent natural catechin extracted from green tea, has attracted extensive research attention in recent years due to its multi-target pharmacological effects. Accumulating evidence demonstrates that EGCG coordinately modulates oxidative stress, neuroinflammation, autophagy-apoptosis homeostasis, excitotoxicity, iron metabolism, and BBB and neurovascular unit (NVU) function to alleviate secondary brain damage and facilitate neurological functional recovery. In addition, EGCG exerts potential adjunct antiplatelet effects via inhibiting platelet activation and thrombosis in ischemic stroke models. Nevertheless, the clinical translation of free EGCG is hindered by poor chemical stability, low systemic bioavailability, limited exposure in cerebral tissue, and insufficient BBB penetration. In recent years, nanodelivery platforms such as liposomes, polymeric nanoparticles, exosomes, and metal–organic frameworks (MOFs) have been proven to markedly enhance EGCG stability, brain-targeted delivery efficiency, and overall bioavailability. These nanocarriers exert enhanced neuroprotective effects and confer synergistic therapeutic benefits when combined with standard agents such as nimodipine in experimental stroke models, offering novel strategies to overcome the translational bottlenecks of free EGCG. This review systematically summarizes research advances in EGCG’s multi-target neuroprotective mechanisms, nanocarrier delivery systems, and translational prospects, focusing on analyzing the strengths and limitations of existing evidence and identifying future research directions. Future investigations should prioritize optimizing brain-targeted delivery platforms, standardizing pharmacokinetic evaluation, unifying therapeutic dose specifications, and conducting high-quality randomized controlled trials to accelerate the clinical transformation of EGCG nanoformulations for precision stroke therapy.