Engineered NK Exosomes Captured Antigens In Situ for Enhanced Tumor Immunotherapy

Natural killer (NK) cells are widely involved in the field of tumor immunotherapy due to their unique killing ability. However, the durability and efficacy of NK-cell monotherapy are facing great challenges owing to the limitation of immunosuppressive tumor microenvironment (TME). NK cell-derived exosomes (Neo) not only play an innate immunomodulatory role similar to NK cells but also emerge as promising antitumor nanocarriers. In this study, an engineered Neo (R@Neo-MN) was designed that encapsulates the multifunctional antitumor drug (Raddeanin a, RA) and modified with maleimide (Mal, M) and mannose (Man, N). The obtained R@Neo-MN could not only exert NK cell-like antitumor function but also induce the immunogenic cell death of tumors to release tumor-associated antigens (TAAs). Furthermore, R@Neo-MN activated the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) to release type I interferons (IFN). Then, R@Neo-MN could capture TAAs through Mal and specifically target dendritic cells (DCs) through Man, thereby promoting the maturation of DCs and enhancing tumor-specific cytotoxic T-cell (CTL)-mediated adaptive immunity. The released IFN further promoted the infiltration and activition of NK cells and CTLs at the tumor site. Our study suggested a novel strategy that harnesses both innate and adaptive immunity for enhanced tumor immunotherapy.