Abstract / Summary
Abstract Mitochondrial dysfunction and impaired mitophagy are key mechanisms underlying neurodegeneration in Parkinson’s disease (PD). The PTEN-induced kinase 1 (PINK1)/Parkin signaling pathway is a primary regulator of mitochondrial quality control and a promising target for disease-modifying therapies. However, clinical translation of small molecules and neuroprotective agents targeting this pathway remains limited by poor aqueous solubility and unfavorable pharmacokinetics due to restricted blood-brain barrier (BBB) penetration. Nanoparticle-based drug delivery systems offer a potential strategy to overcome these barriers. This narrative review evaluates the literature investigating nanoparticle-mediated therapeutic modulation of the PINK1/Parkin pathway in PD. In particular, it focuses on a primary study evaluating a dual-stage nanoparticle platform comprising a B6 peptide-functionalized hyaluronic acid/chitosan nanocarrier conjugated with a PINK1 antibody and loaded with USP30 siRNA. The study reported selective accumulation at depolarized mitochondria through PINK1-dependent targeting, resulting in enhanced mitophagy and reduced neuronal injury. In vivo, treatment was associated with preservation of nigrostriatal dopaminergic neurons and improved motor function in experimental PD models. Despite these promising findings, direct empirical literature combining targeted nanocarriers with canonical PINK1/Parkin signaling remains exceptionally sparse. Existing evidence also relied predominantly on indirect measures of mitochondrial function instead of quantitative assessments of mitophagic flux. Future studies employing standardized mitophagy assays and human induced pluripotent stem cell-derived neuronal models are needed to establish mechanistic efficacy and support clinical translation.