The clinical efficacy of antiretroviral therapy in NeuroAIDS is primarily limited by the low perfusion of the drug to the brain. The objective of the current investigation was to design and develop an in situ mucoadhesive gel loaded with darunavir to assess the feasibility of brain targeting through the intranasal route. Preliminary batches (F1–F9) were prepared and evaluated for various pharmaceutical characteristics. A full factorial design of the experiment was applied to optimize and assess the effect of two influencing variables (Carbopol 934P (X₁) and Poloxamer 407 (X₂)) on the response effects (gelation temperature (Y₁) and % drug release (Y₂) at 8 h). The data demonstrate that both influencing variables affect the response variables significantly (p < 0.05). The optimized formulation (F7) exhibited favorable rheological properties, adequate mucoadhesion, sustained drug release, and greater permeation across the nasal mucosa. An in vitro ciliotoxicity study confirms the nontoxicity of the optimized in situ gel (D7) on the nasal mucosa. An in vivo pharmacokinetic study in rats was performed to assess drug targeting to the brain following the nasal application of the selected in situ gel (D7). Significantly higher (p < 0.0001) C_max (~4-fold) and AUC_0-α (~3.5-fold) values were noticed in the brain after nasal application, as compared to the intravenous route. However, less systemic exposure to darunavir was noticed with nasal therapy, which confirms the low absorption of the drug into the central compartment. Overall, the data here demonstrate that the optimized in situ mucoadhesive nasal gel is effective in targeting darunavir to the brain by the nasal route and could be a viable option for the treatment of NeuroAIDS.

About 1% of people worldwide suffer from epilepsy, a chronic neurological condition characterized by prevalent unprovoked seizures brought on by aberrant neuronal hyperexcitability. Its etiology is complex and includes metabolic imbalances, traumatic injuries, infections (like neurocysticercosis), mutations in genes, and structural abnormalities in the brain (like tumors and hippocampus sclerosis). Antiepileptic drugs (AEDs) that target glutamatergic signaling, GABAergic inhibition, and ion channels are still first-line treatments; however, 30% of patients exhibit pharmacoresistance, illustrating the need for more sophisticated approaches. In refractory situations, neuromodulation (such as vagus nerve stimulation), ketogenic diets, and surgical excision are used. Novel therapeutics are being researched as a result of recent developments in pathophysiology research that have highlighted channels including ion channelopathies, neuroinflammatory cascades, and synaptic reorganization. Innovations include prodrug strategies for targeted activation, implantable devices for extending intraparenchymal drug release, and drug delivery systems enabled by nanotechnology (e.g., solid-lipid nanoparticles, intranasal formulations) that boost blood-brain barrier penetration. Treatment personalization is the goal of emerging strategies like genetic/epigenetic biomarkers and hyperosmolar BBB disruption. Drug-resistant epilepsy therapy continuing to present obstacles despite innovations, emphasizing the critical importance of merging precision medicine, multimodal therapy, and patient-specific biomarkers. With the goal to optimize seizure governance and the quality of life for the people who experience them, this review provides some of the current information on the risk factors, molecular mechanisms, therapeutic advancements, and future directions of epilepsy. Keywords: Epilepsy, Seizures, Antiepileptic drugs (AEDs), Nanotechnology, Drug resistance, Precision medicine