Immunotherapy induced by plant microRNA via ionizable Lipid Nanoparticles delivery enhances chemotherapy effects of Triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC), a highly malignant subtype of breast cancer (BC) that commonly affects females, is occurring at an increasingly younger age, yet there is a lack of clinically effective and safe drugs. The cross-kingdom regulation of plant microRNAs (miRNAs) in cancer immunotherapy has brought new therapeutic hope for TNBC. Here, we searched for plant miRNAs, twa-miRNA152-5p (miR152), from the anticancer plant Taxus wallichiana var. chinensis (Pilger) Florin, which can safely target to regulate human CTLA-4 immune checkpoint across kingdoms. The plant miRNA as a therapeutic requires safe and effective in vivo delivery technologies to prevent its degradation and mediate intracellular delivery. Therefore, we constructed a tumor-targeted folic acid-modified ionizable lipid nanoparticles vector to efficiently encapsulate miR152 and assist in targeted delivery of miR152 to tumor sites. The efficacy, immune antitumor mechanisms and biosafety of miR152 alone or in combination with clinical chemotherapeutic agents to treat TNBC were clarified in vitro and in vivo. The study demonstrated the potential for plant miRNAs cross-kingdom regulation as checkpoint inhibitors to exert immunotherapy in combination with chemotherapeutic drugs for potentiating antitumor efficacy.