Capturing Hydrophilic Chemotherapeutics Agents Into siRNA‐Encapsulated Vesicle‐Like Nanoparticles for Convenient ICB‐Chemo Combination Therapy

Abstract Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co‐delivery of both agents is still highly desirable. In this study, a strategy for co‐delivering small interfering RNA (siRNA) encapsulated in vesicle‐like nanoparticles (VNP siRNA ) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNP siRNA . The resulting VNP siRNA Cp MTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNP siRNA Cp MTO through chemo‐immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co‐delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.