Precision-engineered bacterial nanovectors for synergetic co-delivery to harness cellular senescence and immunomodulation for enhanced tumor eradication

Abstract

The combination of chemotherapy and immunotherapy, for example, doxorubicin and anti-PD-L1 antibody, has been a crucially synergistic cancer treatment. However, the poor intratumoral distribution and limited immunogenicity still impede its antitumor efficacy. To overcome these problems, live bacterial cell factory was introduced as delivery carrier to improve the effect, and further clarify the boosting mechanism of live bacteria in clinical of combination therapy. Herein, we rigorously optimized an anti-PD-L1 nb-expressed E. coli Nissle1917(ECNp) to exert accurate secretion in the hypoxia tumor environment, and doxorubicin-loaded liposome (Dox-Lip) was coated on the surface of EcNp by acid-sensitive imine bond linker. In malignant melanoma models, based on the superior antitumor effect, we found this EcNp-based carrier significantly triggers tumor cell senescence, which increases antigen presentation and causes IFN-γ-dependent immune response, reinforcing the immunogenic death induced by doxorubicin and upregulating the expression of PTEN in tumor cells to increase the sensitivity to anti-PD-L1 nb, playing a “hub” role of cascade-amplified antitumor effect. Moreover, with reliable safety, this EcNp-based hybrid provides a universal platform for the combined penetrant delivery of proteins and small-molecule drugs in advanced cancers.