Cationic Lipids‐Mediated Dual‐Targeting of Both Dendritic Cells and Tumor Cells for Potent Cancer Immunotherapy

Abstract Impaired antigen presentation either in dendritic cells (DCs) or tumor cells impedes the triggering of antitumor immunity or tumor cell killing, resulting in failures of multiple types of cancer immunotherapy. Herein, the strategy of using dual‐targeting nanomedicines to simultaneously improve the presentation of tumor antigens by both DCs and tumor cells is proposed. It is shown that tuning of surface charge of nanoparticles (NPs) by incorporating different amounts of cationic lipids alters the in vivo NP tissue accumulation and cellular targeting profiles. NPs with moderately positive surface charge (≈20 mV) achieve efficient accumulation in tumors and lymph nodes and dual‐targeting to both DCs and tumor cells. As a proof‐of‐concept demonstration, siRNA against YTH N6−methyladenosine RNA binding protein 1 (YTHDF1) is delivered by the dual‐targeting NPs to inhibit excessive antigen degradation in both DCs and tumor cells. For DCs, YTHDF1 downregulation promotes tumor antigen cross‐presentation and cross‐priming of antigen‐specific T cells. For tumor cells, it enhances the presentation of endogenous tumor antigens and hence improves both the recognition and killing of tumor cells by primed antigen‐specific T cells. The dual‐targeting nanomedicines generate efficient antitumor immunity.