Engineered bacteria-mediated augmentation of sialoglycan degradation strategy and immunogenic chemotherapy to boost effective cancer therapy

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.