Spleen-tumor dual-targeting vaccines reshape anticancer landscape by activating both innate and adaptive immunity.

Owing to the reticular structure and dense lymphocyte concentration within the spleen, spleen-targeted vaccines can overcome the challenges faced by conventional vaccines, such as inefficient antigen delivery and delayed immune activation. However, the existing spleen-targeted vaccines are ineffective in preventing and treating immunologically cold tumors. Herein, we develop a spleen/tumor dual-target hybrid vaccine that combines red blood cell membrane-derived vesicles (RBCVs) and bacterial outer membrane vesicles (OMVs) to deliver tumor antigens. This hybrid vaccine utilizes RBCVs to enhance the biosafety of OMVs and endows them with a spleen-targeting ability. Co-delivery of OMVs as adjuvants with tumor antigens to the spleen triggers rapid and robust immune responses, promoting immune memory formation to prevent the development and metastasis of immunologically cold tumors. In addition to acting as vaccine adjuvants, OMVs can target and remodel the immunosuppressive tumor microenvironment by reprogramming tumor-associated macrophages and downregulating regulatory T cells, thereby enhancing the immune responses induced by vaccines and immune checkpoint inhibitors. Because of their antigen-loading flexibility, these versatile vesicles can be used for the spleen-targeted delivery of various protein- or nucleic acid-based antigens, offering a safe and promising strategy for the prevention and treatment of diverse tumors and pathogens.