α-lipoic acid nanoparticles functionalized with RVG29 peptide attenuate seizure-induced neurotoxicity by restoring mitochondrial homeostasis via the PINK1/Parkin pathway.

This study developed a novel nanotherapeutic approach for epilepsy treatment using Rabies Virus Glycoprotein Peptide 29 (RVG29) peptide-functionalized Polyethylene Glycol-Poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles encapsulating the potent antioxidant α-lipoic acid (designated RPP@A). The platform was designed to correct mitochondrial dysfunction by regulating the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway. The engineered nanoparticles exhibited strong brain-targeting capability and efficiently crossed the blood-brain barrier, enabling precise delivery of α-lipoic acid to vulnerable neuronal populations. Comprehensive in vitro and in vivo analyses demonstrated that RPP@A treatment markedly attenuated seizure-induced neurotoxicity by restoring mitochondrial homeostasis and suppressing excessive mitophagy. The antioxidant function of α-lipoic acid, combined with targeted delivery, reduced oxidative stress and neuroinflammation and decreased neuronal apoptosis associated with epileptic pathology. Multi-omics analyses confirmed the central role of PINK1/Parkin signaling in mediating these protective effects. Comparative studies showed that RPP@A outperformed both free α-lipoic acid and non-targeted nanoparticles in reducing seizure frequency and preserving cognitive function, indicating the critical importance of the targeted delivery system. The nanoplatform represents a significant advancement in antioxidant-based therapy for neurological disorders, offering a promising strategy for clinical translation by specifically addressing mitochondrial quality control mechanisms in epilepsy.