Nanotechnology-enhanced neuroprotection: a novel idebenone nanoprodrug conjugate strategy for Parkinson's disease.

Parkinson's disease (PD) is characterized by the progressive loss of dopamine-producing neurons in the substantia nigra pars compacta, and increased oxidative stress, inflammation, and α-synuclein (α-syn) aggregates have been observed in PD brains. Currently, no effective drugs are available for clinical use to prevent the development of PD. Herein, we propose a novel idebenone (IDB) nanoprodrug conjugate strategy for PD treatment. As proof of concept, three bioactive conjugates were designed and synthesized, which subsequently self-assemble into nanomicelles (IDBP NMs). Cellularly, rotenone (Rot) administration induced significant cytotoxicity and apoptosis in PC12 cells, which were closely associated with reduced antioxidant defenses, enhanced lipid peroxidation, and increased levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β). To counteract these deleterious effects, the study evaluated the neuroprotective efficacy of IDBP NMs against Rot-induced neurotoxicity in PC12 cells, demonstrating that these micelles effectively mitigate oxidative stress, inflammation, and α-syn aggregation in Rot-induced models of PD. Furthermore, in Drosophila models, treatment with IDBP NMs significantly regulated reactive oxygen species (ROS) levels in 7-day-old larval brains, thereby exhibiting neuroprotective efficacy. As expected, the Drosophila PD models exhibited the shortest lifespan among all experimental groups; whereas IDBP NMs-treated strains showed significantly extended longevity. In summary, the results indicate that IDBP NMs represent a promising multi-bioactive nanoprodrug for the effective therapy of PD.