Department of Ultrasound, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi' an, People's Republic of China.
Drug Deliv. 2022 Dec;29(1):702-713. doi: 10.1080/10717544.2022.2044937.
Prostate cancer (PCa) responds poorly to routine immunotherapy due to the tumor immunosuppressive microenvironment. Here, we describe an ultrasound-based drug delivery strategy to stimulate potent anti-tumor immunity via exosomes encapsulated with sonosensitizers Chlorin e6 (Ce6) and immune adjuvant R848, namely Exo. Exo was constructed by simple co-incubation of Ce6 and R848 with HEK 293T cell-derived exosomes. The properties of exosomes were not affected after loading Ce6 and R848, and the exosomes were accumulated in the tumor site after intratumoral injection. and assays showed that ultrasonic irradiation enhanced R848-mediated DCs maturation when Exo was engulfed by DCs, as demonstrated by the upregulated expression of CD80 and CD86. Furthermore, these engineered exosomes together with ultrasound irradiation could synergistically reprogram macrophages from an immunosuppressive M2-like phenotype to an anti-tumor M1-like phenotype, further activating effector T cells and reverting the immunosuppressive microenvironment. The exosome delivery strategy not only supplies a paradigm for overcoming side effects of systemic delivery of Ce6 and R848, but also offers an effective combination regimen of cancer immunotherapy.
前列腺癌（PCa）对常规免疫疗法反应不佳，因为肿瘤具有免疫抑制微环境。在这里，我们描述了一种基于超声的药物传递策略，通过用声敏剂氯己定（Ce6）和免疫佐剂 R848 包封的外泌体来刺激有效的抗肿瘤免疫，即 Exo。Exo 通过 Ce6 和 R848 与 HEK 293T 细胞衍生的外泌体简单共孵育构建。负载 Ce6 和 R848 后，外泌体的性质没有受到影响，并且外泌体在肿瘤内注射后积聚在肿瘤部位。和 试验表明，当外泌体被 DC 吞噬时，超声辐射增强了 R848 介导的 DC 成熟，表现为 CD80 和 CD86 的上调表达。此外，这些工程化的外泌体与超声辐射一起可以协同地将巨噬细胞从免疫抑制的 M2 样表型重编程为抗肿瘤的 M1 样表型，进一步激活效应 T 细胞并逆转免疫抑制微环境。外泌体递送策略不仅为克服 Ce6 和 R848 全身递送的副作用提供了范例，而且还为癌症免疫疗法提供了有效的联合治疗方案。
