In situ self-reassembling nanosystem enhances PD-L1 blockade for cancer immunotherapy

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.