Nanostructured Lipid Carriers Enhance Brain Delivery and Antioxidant Efficacy of a Small-Molecule MAO B Inhibitor for Neurodegenerative Disease Therapy

: Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, urgently require new therapeutic strategies. Monoamine oxidase B (MAO B), a mitochondrial enzyme involved in oxidative stress and neurotransmitter metabolism, has emerged as a promising target for neuroprotection. A 5-substituted-1H-indazole derivative (here referred to as compound 1) has been recently identified as a potent and safe MAO B inhibitor with antioxidant and neuroprotective properties. Unfortunately, compound 1 suffers from poor aqueous solubility and chemical stability under hydrolytic conditions, thereby limiting its therapeutic potential. To overcome these drawbacks, nanostructured lipid carriers (NLCs) were developed as delivery systems for compound 1. The coloading of luminescent carbon dots (CDs) together with compound 1 within NLCs further enabled investigation into NLCs' ability to permeate through the artificial blood-brain barrier (BBB) model, allowing a quantitative evaluation of crossing efficiency. Delivery via NLCs resulted in a markedly higher fraction of compound 1 crossing the BBB (∼26%) compared with the free molecule (∼2.6%). Encapsulation also retained antioxidant efficacy in SH-SY5Y cells, while the nanoformulations exhibited a good degree of cell tolerance, with viability remaining above 60% across the tested concentration range. These in vitro findings suggest that the proposed nanoformulation represents a promising strategy to enhance delivery of the investigated small molecule to the central nervous system (CNS), highlighting its potential application in neurodegenerative diseases (NDs).