Plant-derived CTLA-4-targeting miR152 via lipid nanoparticles potentiates doxorubicin efficacy in breast cancer immunochemotherapy

Breast cancer remains a therapeutic challenge due to its high malignancy and the lack of safe and effective treatments. Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated remarkable efficacy against various malignancies by enhancing antitumor immunity when used in combination with chemotherapy. However, conventional antibody-based therapies are associated with adverse effects. Plant-derived microRNAs capable of regulating gene expression represent a highly promising alternative strategy, with substantial potential in disease treatment. In this study, we identified that miR152, a plant-derived microRNA from Taxus×media Rehder, has antitumor activity. Our results demonstrated that miR152 exerts antitumor immune activity by silencing CTLA-4 expression in regulatory T cells. Furthermore, we observed that miR152 maintains a favorable safety profile in normal cells at therapeutic doses, while eliciting direct cytotoxic effects on specific cancer cell lines at higher concentrations. In a mouse tumor model, the combination of anti-CTLA-4 miRNA with doxorubicin significantly improved the efficacy of both monotherapies. Mechanistically, miR152 augmented the antitumor immune response by reducing the proportion of Treg cells within the T-cell compartment and increasing the proportion of CD8 + cytotoxic T cells at tumor sites, enhancing the secretion of Th1- and M1-associated cytokines and suppressing interleukin-10 production. This study reveals for the first time that plant-derived miR152 may serve as a cancer immunotherapy agent in combination with a chemotherapeutic drug to inhibit cancer growth in mammals.