Nose-to-brain delivery of candesartan-loaded nanoemulsion: brain biodistribution and neurobehavioral outcomes in controlled cortical impact-induced traumatic brain injury.

Traumatic brain injury (TBI), defined as a disruption in normal brain function caused by external mechanical force, affects ⁓27-69 million individuals annually worldwide. Despite its high prevalence and association with oxidative stress, neuroinflammation, and neurological deficits, no effective brain-targeted pharmacotherapy has yet been approved for TBI management. Herein, we report an intranasal (IN) candesartan-loaded mucoadhesive nanoemulsion (CND-MNE) designed to enhance nose-to-brain (N2B) delivery and therapeutic efficacy in TBI. The optimized CND-MNE exhibited a mean globule size of 20.98 ± 0.60 nm, spherical morphology, nasal-compatible pH, favourable spreading behaviour, enhanced flux and preserved mucosal integrity. CND-MNE revealed a 2.16- and 3.09-fold enhancement in brain Cmax compared with IN and intravenous suspensions (CND-SUS IN and CND-SUS IV), respectively. Additionally, enhanced N2B transport was confirmed by increased drug targeting efficiency (%DTE, 1.57-fold) and direct transport percentage (1.07-fold) compared to CND-SUS IN. In vivo, CND-MNE at high and low doses (HD, LD) reduced neurological severity scores (⁓4.8-fold and 4.0-fold), improved motor coordination [*P < 0.05 (HD)], spatial memory (****P < 0.0001, HD and LD), and recognition memory [*P < 0.05 (HD)] in the C57BL/6 controlled cortical impact model. Additionally, CND-MNE (HD and LD) markedly decreased brain water content (*P < 0.05) and preserved neuronal architecture. The levels of pro-inflammatory cytokines were lower in the CND-MNE-treated group than in the group treated with IN CND-SUS, indicating reduced neuroinflammation. Collectively, these findings highlight the potential of CND-MNE as an effective non-invasive strategy for targeted brain delivery and neuroprotection in TBI.