Gao Feng, Zhang Zhongkun, Ju Minzi, Bian Liang, Wang Huijuan, Zhao Sibo, Cai Ningbo, Wang Yu, Jia Yanpeng, Shen Ling, Zhang Yuan, Yao Honghong
Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, China.
Adv Sci (Weinh). 2025 Jun;12(21):e2414559. doi: 10.1002/advs.202414559. Epub 2025 Mar 27.
RNA therapeutics have recently shown significant promise in treating a variety of diseases, including cancers, infectious diseases, and genetic disorders. However, their potential in addressing neuropsychiatric disorders has been limited by the lack of an efficient delivery system to the central nervous system (CNS). Here, a novel nanoemulsion platform, perillyl alcohol nanoemulsions (PANEs) is introduced, designed for the therapeutic delivery of circDYM to brain and alleviated depressive-like behaviors. PANEs successfully encapsulated circDYM using cationic lipid compositions, enhancing its delivery efficiency to the mouse brain via its perillyl alcohol phase. The optimized formulation, PANE2-4, significantly improved the brain delivery efficiency of circDYM compared to both free circDYM and standard lipid nanoparticle formulations. Intranasal administration of PANE2-4-circDYM effectively alleviated depressive-like behaviors in the LPS-induced mouse model of depression. This effect is achieved by reducing the CD11bCD45 microglia population and iNOS expression, restoring the expression of protein-95 (PSD-95) and synaptophysin. These findings indicated that PANE represents an efficient platform for delivering circRNAs to the brain, and intranasal administration of PANE2-4-circDYM is a promising strategy for ameliorating LPS-induced depressive-like behaviors.
RNA疗法最近在治疗多种疾病方面显示出巨大潜力，包括癌症、传染病和遗传性疾病。然而，由于缺乏有效的中枢神经系统（CNS）递送系统，它们在治疗神经精神疾病方面的潜力受到限制。在此，引入了一种新型纳米乳剂平台——紫苏醇纳米乳剂（PANEs），其设计用于将circDYM治疗性递送至大脑并减轻抑郁样行为。PANEs使用阳离子脂质组合物成功包裹circDYM，通过其紫苏醇相提高其向小鼠大脑的递送效率。与游离circDYM和标准脂质纳米颗粒制剂相比，优化后的制剂PANE2-4显著提高了circDYM的脑递送效率。经鼻给药PANE2-4-circDYM可有效减轻脂多糖诱导的小鼠抑郁模型中的抑郁样行为。这种效果是通过减少CD11bCD45小胶质细胞数量和诱导型一氧化氮合酶（iNOS）表达，恢复突触后密度蛋白95（PSD-95）和突触素的表达来实现的。这些发现表明，PANEs是一种将环状RNA递送至大脑的有效平台，经鼻给药PANE2-4-circDYM是改善脂多糖诱导的抑郁样行为的一种有前景的策略。
