Baicalein-loaded biomimetic PLGA nanoparticles for ferroptosis-targeted neuroprotection in cerebral ischemia–reperfusion injury

Cerebral ischemia–reperfusion injury (CIRI) contributes to secondary neurological injury following ischemic stroke, with ferroptosis increasingly recognized as an important mechanism involving iron dysregulation, lipid peroxidation, impaired glutathione-dependent antioxidant defenses, and mitochondrial dysfunction. This review summarizes the molecular mechanisms of ferroptosis in CIRI, evaluates evidence regarding baicalein, a bioactive flavonoid from Scutellaria baicalensis Georgi, and examines biomimetic nanocarrier strategies for ischemic stroke. A structured literature search was conducted in PubMed, Scopus, and Web of Science for publications from January 2015 to January 2026, focusing on CIRI and ferroptosis; baicalein and cerebral ischemia/neuroprotection; baicalein and ferroptosis; and poly(lactic-co-glycolic acid) (PLGA)-based and biomimetic nanocarrier strategies. The literature indicates that ferroptosis is closely associated with oxidative stress, iron dysregulation, impaired antioxidant defense, lipid peroxidation, mitochondrial dysfunction, and neuroinflammation in CIRI. Experimental evidence suggests that baicalein may modulate ferroptosis-related pathways, including those involving glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4), while also influencing oxidative and inflammatory responses. PLGA-based and biomimetic nanocarriers may improve the delivery of neuroprotective compounds, and platelet membrane camouflage may provide additional biomimetic properties relevant to targeted delivery. However, direct evidence integrating baicalein, PLGA-based delivery, and platelet membrane camouflage into a single ferroptosis-targeted platform for CIRI remains limited. This proposed integration represents a hypothesis-driven direction for future preclinical research. Further studies are needed to establish mechanistic validity, optimize delivery characteristics, evaluate pharmacokinetics and biosafety, and determine therapeutic efficacy in clinically relevant models.