Although immune checkpoint inhibitors (ICIs) have made great progress in cancer treatment, their off-tumor distribution, low affinity of traditional ICIs and insufficient T cells infiltration at tumor site limit immunotherapeutic efficacy. Herein, we engineer a highly specific and effective PD-L1 inhibitor (PEC) that modulates the level of binding sites with PD-L1. Specifically, PEC is a hybrid system composed of E. coli membrane expressing PD-L1 binding protein and cancer cell membrane. Notably, PEC can target the tumor site, produce oxygen in response to H2O2, rupture into membrane fragments, and reassemble to form vesicles retaining the PD-L1 binding protein. Through in situ fracture and reassembly, PEC transforms from a hybrid membrane to a single E. coli membrane, leading to the increased density of PD-L1 binding protein. Consequently, the reassembled vesicles can bind to more PD-L1 on tumor cells and induce its degradation in lysosomes. Furthermore, the cGAS-STING signaling activators HZD is encapsulated into PEC to promote T cells infiltration. We demonstrate that PEC@HZD achieves sequential T cells recruitment and functional enhancement, thus stimulating a powerful antitumor immune response. This work provides a new perspective on tailoring ICIs to improve cancer immunotherapy.

中文翻译：

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原位自组装纳米系统增强 PD-L1 阻断剂用于癌症免疫治疗


尽管免疫检查点抑制剂 （ICI） 在癌症治疗方面取得了长足的进步，但其肿瘤外分布、传统 ICIs 的低亲和力和肿瘤部位 T 细胞浸润不足限制了免疫治疗效果。在此，我们设计了一种高度特异性和有效的 PD-L1 抑制剂 （PEC），可调节与 PD-L1 结合位点的水平。具体来说，PEC 是由表达 PD-L1 结合蛋白的大肠杆菌膜和癌细胞膜组成的杂交系统。值得注意的是，PEC 可以靶向肿瘤部位，响应 H2O2 产生氧气，破裂成膜片段，并重新组装形成保留 PD-L1 结合蛋白的囊泡。通过原位断裂和重组，PEC 从杂交膜转变为单个大肠杆菌膜，导致 PD-L1 结合蛋白的密度增加。因此，重组的囊泡可以与肿瘤细胞上的更多 PD-L1 结合并诱导其在溶酶体中的降解。此外，cGAS-STING 信号转导激活剂 HZD 被封装到 PEC 中以促进 T 细胞浸润。我们证明PEC@HZD实现了连续的 T 细胞募集和功能增强，从而刺激了强大的抗肿瘤免疫反应。这项工作为定制 ICIs 以改善癌症免疫治疗提供了新的视角。