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

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

  • Free Radic Biol Med. 2025 Dec 23:245:201-222. doi: 10.1016/j.freeradbiomed.2025.12.037.
Jianxun Hou 1,  Lei Hao 2,  Wei Du 1,  Qiuyu Su 3,  Qijiang Xiong 1,  Wang Zhao 4,  Zhao Yang 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China.
  • 2 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 3 Department of Neurology, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China.
  • 4 Department of Neurology, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China. Electronic address: [email protected].
  • 5 Department of Neurology, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China. Electronic address: [email protected].
PMID: 41448258 DOI: 10.1016/j.freeradbiomed.2025.12.037
Abstract

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.

Keywords

Mitophagy; Oxidative stress; PINK1/Parkin pathway; Targeted nanoparticles; α-lipoic acid.

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