Intranasal Mitochondria-Targeted Rosmarinic Acid Selenium Nanoparticles Restore Mitochondrial Function and Attenuate Dopaminergic Neurodegeneration in Parkinson’s Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, mitochondrial dysfunction, oxidative stress, and α-synuclein pathology, highlighting the need for mitochondria-targeted neuroprotective strategies. Here, we developed a mitochondria-targeted intranasal nanotherapeutic system comprising rosmarinic acid (RA)-loaded selenium nanoparticles (RASNPs) surface-functionalized with triphenylphosphonium (TPP)-conjugated chitosan (TCS-RASNPs) to enhance nose-to-brain delivery and improve mitochondrial function. TCS-RASNPs exhibited a spherical morphology, a uniform particle size distribution (140.13 ± 0.40 nm), a narrow polydispersity, and a positive surface charge (33.7 ± 0.75 mV), indicating good colloidal stability. Spectroscopic characterization confirmed successful RA loading and surface functionalization. Moreover, TCS-RASNPs enhanced antioxidant activity and sustained drug release compared with free RA and unmodified RASNPs. In neuronal cells, TCS-RASNPs significantly enhanced neuronal survival, reduced apoptosis, attenuated intracellular and mitochondrial reactive oxygen species (ROS) generation, and improved mitochondrial membrane potential under 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Confocal microscopy further confirmed efficient mitochondrial localization of TCS-RASNPs. Pharmacokinetic and biodistribution studies demonstrated prolonged retention of RA and significantly higher brain RA levels following intranasal administration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian mice, TCS-RASNPs increased tyrosine hydroxylase (TH) expression, reduced α-synuclein (SNCA) expression, and normalized oxidative stress biomarkers in the substantia nigra pars compacta (SNpc) and striatum (STR) regions. Together, these findings demonstrate that TCS-RASNPs facilitate mitochondrial targeting and nose-to-brain delivery, thereby representing a promising nanotherapeutic approach for the management of PD.