Mechanistic insights into a thermoresponsive <i>in situ</i> nanoemulgel of azilsartan medoxomil for intranasal delivery: a promising nanotherapeutic approach to target dementia

Cognitive impairment and dementia have become a global burden, distressing millions of elderly and accounting for the progressive loss of neurons in the brain, affecting multiple cortical centers. The renin-angiotensin system and its receptors, widely distributed within the brain, can serve as potential targets in treating dementia by diminishing oxidative radical generation and neuronal inflammation and increasing the integrity of the blood-brain barrier. The present study delves into the formulation and optimization of a thermoresponsive azilsartan medoxomil (AZL-M)-loaded <i>in situ</i> nanoemulgel for targeted nose-to-brain delivery, addressing the challenge of restricted entry of angiotensin receptor blockers (ARBs) to the brain due to their low BBB permeability. The formulation components and mixing time for the AZL-M nanoemulsion were optimized using a Box-Behnken design approach, followed by optimization of various characterization parameters. Among the optimized gels, formulation F20 demonstrated superior characteristics for intranasal delivery, exhibiting gelation at 33.4 °C (nasal temperature), a pH of 6.21 ± 0.35, a droplet size of 160 ± 3.72 nm, a PDI of 0.21 ± 0.001, and a zeta potential of -11.2 ± 0.85 mV, with suitable viscosity at 15 °C and 35 °C. Moreover, F20 achieved 60.4% ± 5.69% cumulative drug release after 8 h, together with the highest cumulative permeation (505 ± 55.15 μg cm^-2), indicating its greater efficacy in permeating nasal mucosal cells. Safety studies confirmed the biocompatibility of F20 and reduction in ROS generation with enhanced SH-SY5Y cell viability. <i>In vivo</i> studies displayed improved cognitive functions together with increased antioxidant enzyme activities (SOD, GSH, and catalase), reduced malondialdehyde levels, and enhanced neuronal count in brain histopathological studies. Furthermore, the levels of brain inflammatory markers (TNF-α and IL1-β) decreased, together with the upregulation of brain-derived neurotrophic factor (BDNF) levels, suggesting marked neuroprotection. Thus, the intranasally delivered AZL-M nanoemulgel emerges as safe and effective for treating dementia and related disorders.