Sialic acid, as the new immunosuppressive molecule, is positively correlated with tumor progression, metastasis, and drug resistance. Although targeting desialylation strategy has promising implications for regulating immunosuppressive environment and sensitizing chemotherapy, delivery strategies that integrate the amplifying effects of desialylation and immunogenic chemotherapy are still unexplored. Here, we engineered an Escherichia coli Nissle 1917 hybrid (SSE@ZIF-90/Oxa) to integrate the co-delivery of sialidase and immunogenic cell death inducers which were expected to boost strong antitumor response. In the tumor-hypoxic environment, engineered SSE bacteria exert hypoxia-responsive sialidase expression and periodic lysis to release sialidase, disrupting the sialoglycan-mediated immune suppression. ZIF-90/Oxa was hybridized on the surface of SSE to further induce ICD effect to recruit more infiltration of immune cells. In melanoma models in male mice, this SSE@ZIF-90/Oxa facilitated the co-delivery of sialidase and Oxa both deeply penetrated into and across tumor, suppressed the tumor, and prolonged the survival time of mice, by markedly increasing mature DCs, TNF-α+ CD8+ T cells, and M1 macrophages, while reducing PD-1+CD8+ T cells and Tregs, indicating effective activation of anti-tumor immune cells. Thus, our study provides an intelligent biohybrid therapeutic platform for boosting the combined effect of desialylation-based immunotherapy and immunogenic chemotherapy.

中文翻译：

---

工程细菌介导的唾液聚糖降解策略和免疫原性化疗增强，以促进有效的癌症治疗


唾液酸作为新型免疫抑制分子，与肿瘤进展、转移、耐药等呈正相关。尽管靶向去唾液酸化策略对于调节免疫抑制环境和增敏化疗具有广阔的前景，但整合去唾液酸化和免疫原性化疗的放大效应的递送策略仍未被探索。在这里，我们设计了大肠杆菌 Nissle 1917 杂交体 (SSE@ZIF-90/Oxa)，以整合唾液酸酶和免疫原性细胞死亡诱导剂的共同递送，预计这将增强强烈的抗肿瘤反应。在肿瘤缺氧环境中，工程SSE细菌发挥缺氧响应性唾液酸酶表达并定期裂解以释放唾液酸酶，破坏唾液聚糖介导的免疫抑制。 ZIF-90/Oxa在SSE表面杂交，进一步诱导ICD效应，招募更多免疫细胞浸润。在雄性小鼠黑色素瘤模型中，SSE@ZIF-90/Oxa 促进唾液酸酶和 Oxa 共同递送，深入渗透到肿瘤中并穿过肿瘤，抑制肿瘤，并通过显着增加成熟 DC 延长小鼠的生存时间。 TNF-α+ CD8+ T 细胞和 M1 巨噬细胞，同时减少 PD-1+ CD8+ T 细胞和 Tregs，表明抗肿瘤免疫细胞的有效激活。因此，我们的研究提供了一个智能生物混合治疗平台，用于增强基于脱唾液酸化的免疫疗法和免疫原性化疗的联合效果。