Bispecific cellular nanovesicles potentiate NK cell immunity against gastric cancer

Natural killer (NK) cells are potent immune modulators that can quickly lyse tumor cells without prior sensitization or recognition of specific tumor antigens. However, NK cells in the tumor microenvironment are frequently dysfunctional. Despite advances in cytokine therapy and NK cell adoptive transfer, tumor-expressed ligands that interact with NK cell-expressed checkpoint receptors can greatly suppress NK cell-mediated tumor lysis, leading to suboptimal therapeutic outcomes. Here we explored a new approach of utilizing cellular nanovesicles (NVs) as artificial controllers of cellular immunity to redirect and activate NK cells for tumor eradication. Through this strategy, we engineered HEK293 cell-derived NVs genetically modified to display two distinct types of surface monoclonal antibodies (mAbs), namely human cluster of differentiation 16 (CD16) and human epidermal growth factor receptor 2 (HER2) antibodies, generating dual aCD16/aHER2 NVs that simultaneously target CD16-expressing NK cells and HER2-expressing gastric cancer cells. Following thorough characterization, the aCD16/aHER2 NVs exhibited highly potent and specific anti-tumor activity both in vitro and in vivo. This preclinical work demonstrates the feasibility of using dual-targeting NVs to navigate functional NK cells to recognize and eliminate gastric cancers, presenting aCD16/aHER2 NVs as an effective and versatile platform for cancer immunotherapy.