免疫疗法彻底改变了癌症治疗的格局。然而，单一的免疫疗法只对少部分患者有效。与抗肿瘤协同作用的联合免疫疗法具有相当大的潜力来提高治疗效果。然而，目前很少研究联合免疫疗法的协同、加法或拮抗的抗肿瘤效应。在此，我们通过在M1巨噬细胞衍生的外泌体（EVs）表面包覆PAK4靶向siRNA和光活性聚乙烯亚胺组装的纳米复合核心，建立了一种新型的联合癌症治疗模式，通过协同作用p21激活的激酶4（PAK4）沉默与免疫性光疗。工程EVs诱导了强效的PAK4沉默和强大的免疫性光疗，在体外和体内中展示了有效的抗肿瘤效果。此外，联合治疗的抗肿瘤协同作用量化分析采用CompuSyn方法进行。组合指数（CI）和等效曲线结果证实了联合治疗存在抗肿瘤协同作用。此外，剂量减少指数（DRI）显示了良好的剂量减少，揭示了工程EVs的较低毒性和较高的生物相容性。总的来说，本研究展示了一种通过在工程EVs中结合PAK4沉默和免疫性光疗来协同增强的癌症治疗模式，对于提高癌症免疫疗法的治疗效果具有潜力。© 2023 中国医药学会和中国医学科学院药物研究所。Elsevier B.V.制作和托管。

Immunotherapy has revolutionized the landscape of cancer treatment. However, single immunotherapy only works well in a small subset of patients. Combined immunotherapy with antitumor synergism holds considerable potential to boost the therapeutic outcome. Nevertheless, the synergistic, additive or antagonistic antitumor effects of combined immunotherapies have been rarely explored. Herein, we established a novel combined cancer treatment modality by synergizing p21-activated kinase 4 (PAK4) silencing with immunogenic phototherapy in engineered extracellular vesicles (EVs) that were fabricated by coating M1 macrophage-derived EVs on the surface of the nano-complex cores assembled with siRNA against PAK4 and a photoactivatable polyethyleneimine. The engineered EVs induced potent PAK4 silencing and robust immunogenic phototherapy, thus contributing to effective antitumor effects in vitro and in vivo. Moreover, the antitumor synergism of the combined treatment was quantitatively determined by the CompuSyn method. The combination index (CI) and isobologram results confirmed that there was an antitumor synergism for the combined treatment. Furthermore, the dose reduction index (DRI) showed favorable dose reduction, revealing lower toxicity and higher biocompatibility of the engineered EVs. Collectively, the study presents a synergistically potentiated cancer treatment modality by combining PAK4 silencing with immunogenic phototherapy in engineered EVs, which is promising for boosting the therapeutic outcome of cancer immunotherapy.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.