Delivering therapeutic agents to the brain remains a major challenge due to the restrictive nature of the blood–brain barrier (BBB). Intranasal administration has emerged as a promising, non-invasive approach that bypasses the BBB and facilitates direct nose-to-brain transport via the olfactory and trigeminal pathways. In this study, we developed a nanostructured lipid carrier (NLC) system for the intranasal delivery of dolutegravir sodium, a potent integrase inhibitor, with the goal of enhancing brain bioavailability for the treatment of neuroHIV and related central nervous system (CNS) complications. The NLCs were optimized for particle size, polydispersity index (PDI), and drug incorporation efficiency. The optimized formulation exhibited a mean particle size of 90.3 nm and a PDI of 0.23, indicating a uniform size distribution suitable for nasal administration. Cytocompatibility studies conducted on a model cell line confirmed the safety of the formulation. To enhance mucosal retention and enable sustained drug release, the NLC dispersion was incorporated into a thermosensitive in situ gel. Rhodamine B, a fluorescent dye, was used as a model tracer for qualitative assessment of biodistribution. In vivo studies in rats showed a time-dependent accumulation of rhodamine B in brain tissues following a single intranasal dose of the NLC in situ gel. Peak fluorescence was observed at 2 hours post-administration, confirming efficient brain targeting via the intranasal route. In conclusion, the developed in situ gel-based NLC system demonstrates potential as a non-invasive and effective platform for targeted brain delivery. This approach offers promising therapeutic opportunities for managing CNS disorders and warrants further investigation with clinically relevant drug molecules.
