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Pore-forming Gasdermin protein-induced pyroptosis in tumor cells promotes anti-tumor immune response through the release of pro-inflammatory cytokines and immunogenic substances after cell rupture. However, endosomal sorting complexes required for transport (ESCRT) III-mediated cell membrane repair significantly diminishes the tumor cell pyroptosis by repairing and subsequently removing gasdermin pores. Here, we show that blocking calcium influx-triggered ESCRT III-dependent membrane repair through a biodegradable nanoparticle-mediated sustained release of calcium chelator (EI-NP) strongly enhances the intracellularly delivered GSDMD-induced tumor pyroptosis via a bacteria-based delivery system (VNP-GD). An injectable hydrogel and a lyophilized hydrogel-based cell patch are developed for peritumoral administration for treating primary and metastatic tumors, and implantation for treating inoperable tumors respectively. The hydrogels, functioning as the local therapeutic reservoirs, can sustainedly release VNP-GD to effectively trigger tumor pyroptosis and EI-NP to prevent the ESCRT III-induced plasma membrane repair to boost the pyroptosis effects, working synergistically to augment the anti-tumor immune response.

胞吐作用相关网格蛋白重分组装复合体 III（ESCRT-III）介导的细胞膜修复显著降低了肿瘤细胞的细胞焦亡：细胞焦亡是一种依赖 Gasdermin 的程序性细胞死亡方式，在肿瘤免疫中发挥重要作用。Gasdermin 蛋白诱导的肿瘤细胞焦亡可通过破裂细胞释放促炎细胞因子和免疫原性物质，从而促进抗肿瘤免疫反应。然而，胞吐作用相关网格蛋白重分组装复合体 III（ESCRT-III）介导的细胞膜修复会显著减少肿瘤细胞焦亡，其机制是通过修复并随后去除 Gasdermin 孔。

基于纳米颗粒的递送系统（VNP-GD）：在这里，我们通过一种基于细菌的递送系统（VNP-GD）证明，通过生物降解纳米颗粒介导的钙螯合剂（EI-NP）的持续释放来阻断钙流入触发的 ESCRT III 依赖性细胞膜修复，可强烈增强细胞内递送的 GSDMD 诱导的肿瘤细胞焦亡。此外，我们还开发了一种可注射水凝胶和一种冻干水凝胶基细胞贴片，分别用于肿瘤周围给药以治疗原发性和转移性肿瘤，以及用于不可手术肿瘤的植入治疗。这些水凝胶作为局部治疗储库，可以持续释放 VNP-GD 以有效触发肿瘤细胞焦亡，并释放 EI-NP 以防止 ESCRT III 诱导的质膜修复，从而增强焦亡效应，协同增强抗肿瘤免疫反应。