Development of a Nanostructured Lipid Carrier Drug Delivery System for the Essential Oil of Zanthoxylum Bungeanum Maxim. To Effectively Ameliorate Depression

ABSTRACT Zanthoxylum bungeanum Maxim., a traditional Chinese cash crop, produces pericarps (huajiao) that are widely used as condiments and herbal medicines. Zanthoxylum bungeanum Maxim. essential oil (HEO), one of the primary bioactive components, has potential antidepressant properties, but faces challenges in pharmaceutical development due to its instability and low oral bioavailability. To address these limitations, this study developed a nanostructured lipid carrier encapsulating HEO (HEO‐NLC) via a melt‐ultrasonic method. The critical formulation parameters were systematically optimized through single‐factor analysis and response surface methodology. Biocompatibility assessments, including histopathological evaluation, confirmed the safety profile of HEO‐NLCs in vivo. Compared with HEO, HEO‐NLC demonstrated superior antidepressant efficacy in a chronic unpredictable mild stress (CUMS) model. Mechanistic studies revealed that HEO‐NLCs enhanced the systemic absorption and blood‒brain barrier penetration of linalool, a key bioactive terpene, as evidenced by 3.29‐fold and 2.07‐fold increases in the serum and brain concentrations, respectively. Furthermore, HEO‐NLCs attenuated neuronal apoptosis by modulating the Bcl‐2/Bax balance and suppressing caspase‐3 activation. These findings establish HEO‐NLCs as promising nanoformulations to overcome the pharmaceutical limitations of herbal essential oils, providing a foundation for developing oral antidepressants with enhanced stability and bioavailability. Practical Applications This technology enables the creation of stable, natural antidepressant supplements using encapsulated Zanthoxylum bungeanum essential oil. The improved formulation can be developed into oral capsules or liquid drops, offering a longer‐lasting and more effective option for mood support than traditional herbal extracts, with reduced digestive discomfort. The enhanced shelf life of these NLCs under refrigerated conditions makes it suitable for commercial production and distribution.