Activation of the innate immune system and natural killer (NK) cells has been a key effort in cancer immunotherapy research. Here, we report a nanoparticle-based trispecific NK cell engager (nano-TriNKE) platform that can target epidermal growth factor receptor (EGFR)–overexpressing tumors and promote the recruitment and activation of NK cells to eradicate these cancer cells. Moreover, the nanoengagers can deliver cytotoxic chemotherapeutics to further improve their therapeutic efficacy. We have demonstrated that effective NK cell activation can be achieved by the spatiotemporal coactivation of CD16 and 4-1BB stimulatory molecules on NK cells with nanoengagers, and the nanoengagers are more effective than free antibodies. We also show that biological targeting, either through radiotherapy or EGFR, is critical to the therapeutic effects of nanoengagers. Last, EGFR-targeted nanoengagers can augment both NK-activating agents and chemotherapy (epirubicin) as highly effective anticancer agents, providing robust chemoimmunotherapy.

先天免疫系统和自然杀伤（NK）细胞的激活一直是癌症免疫治疗研究的关键工作。在此，我们报告了一种基于纳米颗粒的三特异性 NK 细胞接合器 (nano-TriNKE) 平台，该平台可以靶向表皮生长因子受体 (EGFR) 过度表达的肿瘤，并促进 NK 细胞的招募和激活，从而根除这些癌细胞。此外，纳米催化剂可以提供细胞毒性化疗药物，以进一步提高其治疗效果。我们已经证明，通过纳米接合剂对NK细胞上CD16和4-1BB刺激分子的时空共激活可以实现有效的NK细胞激活，并且纳米接合剂比游离抗体更有效。我们还表明，生物靶向（无论是通过放射疗法还是 EGFR）对于纳米接合剂的治疗效果至关重要。最后，靶向 EGFR 的纳米接合剂可以增强 NK 激活剂和化疗（表阿霉素）作为高效抗癌药物的作用，提供强大的化学免疫疗法。