Li Li, Luo Mei, Zhou Lifang, Wang Yanhong, Jiao Yaoge, Wang Chunting, Gong Changyang, Cen Xiaobo, Yao Shaohua
Laboratory of Biotherapy, National Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Renmin Nanlu 17, Chengdu 610041, Sichuan, China.
Mental Health Center and Center for Preclinical Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China.
Int J Pharm. 2025 Mar 15;672:125282. doi: 10.1016/j.ijpharm.2025.125282. Epub 2025 Jan 27.
Lipid nanoparticles (LNPs) are among the most promising non-viral mRNA delivery systems for gene therapeutic applications. However, the in vivo delivery of LNP-mRNA remains challenging due to multiple intrinsic barriers that hinder LNPs from reaching their target cells. In this study, we sought to enhance LNP delivery by manipulating intrinsic regulatory mechanisms involved in their metabolism. We demonstrated that activation of the glucocorticoid pathway significantly increased the systemic delivery of LNP-mRNA in both mice and monkeys, achieving up to a fourfold improvement. This enhancement was primarily attributed to the glucocorticoid-mediated inhibition of macrophage phagocytosis in circulation and the liver, which resulted in higher LNP accumulation in hepatocytes. Consequently, glucocorticoid activation improved the therapeutic efficacy of LNP-based protein replacement and CRISPR/Cas9 genome editing therapies. Together, these findings establish a practical strategy to enhance the systemic delivery of RNA-based protein replacement and genome editing therapeutics, highlighting the potential of manipulating endogenous mechanisms to optimize exogenous gene delivery.
脂质纳米颗粒（LNPs）是基因治疗应用中最有前景的非病毒mRNA递送系统之一。然而，由于多种内在障碍阻碍LNPs到达靶细胞，LNP-mRNA的体内递送仍然具有挑战性。在本研究中，我们试图通过操纵参与其代谢的内在调节机制来增强LNP递送。我们证明，糖皮质激素途径的激活显著增加了LNP-mRNA在小鼠和猴子体内的全身递送，提高了四倍之多。这种增强主要归因于糖皮质激素介导的循环和肝脏中巨噬细胞吞噬作用的抑制，这导致肝细胞中LNP积累增加。因此，糖皮质激素激活提高了基于LNP的蛋白质替代和CRISPR/Cas9基因组编辑疗法的治疗效果。总之，这些发现建立了一种增强基于RNA的蛋白质替代和基因组编辑疗法全身递送的实用策略，突出了操纵内源性机制以优化外源性基因递送的潜力。
