Hydroxychloroquine-Derived Ionizable Lipid Facilitates Spleen-Tropic Transfection and Enhances Cancer Immunotherapy

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 <i>in vitro</i> and <i>in vivo</i>. 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.