Engineering selenium-loaded NK-bacterial hybrid vesicle activate innate and adaptive immunity for triple-negative breast cancer therapy.

The integration of innate immunity and adaptive immune mechanisms represents a promising strategy for enhancing anti-tumor immune responses. Natural killer (NK) cells, as key effector cells bridging innate and adaptive immunity, play a critical role in the early anti-tumor immune response. However, their functions are often significantly impaired by oxidative stress and immunosuppressive factors within the tumor microenvironment (TME). Additionally, crosstalk between NK cells and dendritic cells (DCs), macrophages, and T cells is disrupted, further weakening antigen presentation and T cell activation, thereby hindering the effective establishment of adaptive immune responses. To address this challenge, we innovatively integrated NK cell-derived exosomes (Neo) with selenium-loaded outer membrane vesicles derived from E. coli (Se@OMV) to construct a hyaluronic acid (HA)-targeted hybrid exosome (Se@NOV-HA). This system enhanced the secretion of functional proteins in NK cells by scavenging intracellular reactive oxygen species (ROS), while simultaneously inducing ROS-dependent apoptosis and immunogenic cell death (ICD) in tumor cells. Furthermore, Se@NOV-HA activated the cysteinyl aspartate-specific protease (caspase) pathway to directly kill tumor cells and reprogram the phenotype of tumor-associated macrophages (TAMs), thereby ameliorating the immunosuppressive microenvironment. Ultimately, this composite system potentiated NK cell activity and reinforces the DCs-T cell immune axis, establishing a triple-synergistic antitumor network characterized by innate immune activation, T cell response enhancement, and TME remodeling. In summary, Se@NOV-HA not only directly rescued NK cell dysfunction but also reshaped the immune microenvironment to ignite a multilayered antitumor cascade, offering a new avenue for the concomitant activation of both innate and adaptive antitumor immunity.