Reactive Oxygen Species-Responsive Targeted Polydopamine-Rosmarinic Acid Nanotherapeutics for Ferroptosis-Driven Parkinson's Disease Modulation in Caenorhabditis elegans

Parkinson's disease (PD), a progressive neuropathy marked by abnormal α-synuclein (α-Syn) deposition and oxidative stress-driven degeneration of dopaminergic neurons (DA neurons), remains inadequately addressed by current palliative strategies that primarily provide symptomatic relief, emphasizing the need for enhanced therapeutic modalities. In particular, ferroptosis, an iron cell death mechanism, is a key driver of PD pathogenesis, and its modulation represents a feasible therapeutic target. Here, we designed a neuromelanin-mimetic polydopamine (PDA)-based nanomedicine to attenuate ferroptosis-associated oxidative stress and iron dysregulation in PD by functionalizing PDA nanoparticles with triphenylphosphonium (TPP) for mitochondrial targeting and loading rosmarinic acid (RA), yielding TPRA nanoparticles (TPRA NPs). TPRA NPs combine the antioxidative and iron-chelating attributes of RA with reactive oxygen species (ROS)-responsive release properties. TPRA NPs exhibited efficient RA loading, sustained ROS-triggered release, effective iron chelation, and comprehensive free radical neutralization. In vivo evaluations in Caenorhabditis elegans demonstrated that TPRA NPs were well-tolerated at concentrations up to 64 μg/mL, with no detectable adverse effects, and enhanced healthspan and stress resistance. TPRA NPs markedly attenuated ferroptosis-associated markers by decreasing excess iron, lipid peroxidation, and ROS while simultaneously restoring glutathione balance, locomotor performance, and modulating ferroptosis-associated genes in worms induced with 1-methyl-4-phenylpyridinium (MPP + ), erastin, or iron. Furthermore, these nanoparticles preserved the viability of DA neurons and restored neurobehavioral function and mitochondrial integrity. TPRA NPs reduced α-synuclein deposition, lengthened lifespan, and activated SKN-1 signaling while upregulating mitophagy-related genes in α-Syn expressing NL5901 worms, thereby strengthening endogenous defenses. These findings establish targeted, natural polyphenol-loaded biomimetic nanoparticles as a potential approach to mitigate ferroptosis-associated stress in PD.