Unlocking the potential of lipid-based nanoparticles for intranasal drug delivery in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, α-synuclein aggregation, mitochondrial dysfunction, and persistent neuroinflammation. Despite symptomatic advances, the blood-brain barrier (BBB) continues to restrict the delivery of many potentially disease-modifying agents. Intranasal (IN) administration, by exploiting direct olfactory and trigeminal pathways, offers a non-invasive means to bypass the BBB. When combined with lipid-based nanoparticles (LNPs), this route has shown promise in enhancing central nervous system targeting, drug protection, and controlled release. This review examines the preclinical landscape of LNP-enabled IN delivery for PD, highlighting applications across dopamine replacement, anti-aggregatory strategies, antioxidant and anti-inflammatory therapies, and neurotrophic or gene-based interventions. In animal models, IN-LNP systems have achieved significant increases in brain uptake compared to free drug, with associated improvements in behavioral metrics such as motor coordination and dopaminergic neuron survival. However, these encouraging findings are drawn almost exclusively from rodent studies; no clinical trials have yet evaluated IN-LNP platforms in human PD. Major translational challenges persist, including interspecies anatomical differences, limited long-term safety data, formulation variability, and regulatory complexity. As such, while IN-LNP strategies represent a promising and versatile approach, their clinical potential is contingent on rigorous future validation.