NeuroAIDS refers to the spectrum of neuropsychiatric complications observed in approximately 30–50% of HIV/AIDS patients. Although the advent of antiretroviral therapy has reduced the severity of AIDS, mild cognitive deficits persist in nearly half of treated patients, highlighting limitations in central nervous system (CNS) drug delivery. These limitations are attributed to poor blood-brain barrier (BBB) permeability, P-glycoprotein efflux, low solubility, first-pass metabolism, and short half-lives of many ART drugs. Nose-to-brain drug delivery has emerged as a promising alternative, bypassing the BBB via olfactory and trigeminal pathways. This route offers direct CNS access while minimizing systemic exposure. Factors such as drug molecular weight, lipophilicity, pH, osmolality, viscosity, particle size, and surface charge significantly influence nasal drug absorption and brain targeting. Approaches to optimize nose-to-brain delivery include the use of prodrugs, permeation enhancers, mucoadhesive agents, enzyme inhibitors, and P-glycoprotein inhibitors. Despite encouraging preclinical data, challenges remain, including mucociliary clearance, enzymatic degradation, and species-specific anatomical variations that hinder translational research. A rational formulation design that considers physiological and physicochemical barriers is essential for clinical success. Nanocarriers—including nanovesicles, solid lipid nanoparticles (SLNs), and microemulsions—offer several advantages: they protect drugs from enzymatic degradation, improve solubility and stability, enable controlled release, and enhance mucoadhesion and uptake across the nasal mucosa. Overall, intranasal delivery systems, particularly those employing nanocarriers and functional excipients, offer a novel and efficient approach to managing NeuroAIDS by enhancing ART bioavailability in the CNS and improving drug access to HIV reservoirs in the brain.
