Hydroxychloroquine-Derived Ionizable Lipid Facilitates Spleen-Tropic Transfection and Enhances Cancer Immunotherapy
Jiaqi Fan, Wei Qi, Pengcheng Yuan, Bing Xiao, Shasha Yao, Haoran Xu, Jiwei Liu, Ruoshui Li, Youqing Shen, Nigel K.H. Slater, Jianbin Tang
Abstract
High Resolution Image Download MS PowerPoint Slide The success of SARS-CoV-2 mRNA vaccines has boosted their development against various diseases, especially tumors. However, their clinical application is hindered by limited therapeutic efficacy and non-negligible side effects. Many studies attempt to improve therapeutic effect against tumors by using spleen-tropism mRNA delivery systems. Herein, we develop lipid nanoparticles (LNPs) based on hydroxychloroquine (HCQ)-derived ionizable lipid as a spleen-tropism mRNA delivery system that simultaneously modulates the tumor immune-suppressive microenvironment. The screened HCQ LNPs exhibit high mRNA transfection efficiency both in vitro and in vivo . Surprisingly, the HCQ LNP can achieve spleen-tropic transfection after systemic administration, which is conducive to immune cells for antigen presentation. In addition, HCQ LNP passively targeted to tumors significantly repolarizes tumor-associated macrophages to the M1 phenotype, thereby modulating the tumor microenvironment. Therefore, compared to the commercial MC-3 LNP/mOVA, HCQ LNP/mOVA shows significantly improved prophylactic and therapeutic antitumor efficacy and antimetastatic effect. HCQ LNP/mOVA demonstrates a multifaceted strategy that enhances the therapeutic efficacy of mRNA tumor vaccines through functional mRNA delivery system design.