Programmable engineered bacteria as sustained-releasing antibody factory in situ for enhancing tumor immune
Xiao-Ting Xie1, Meng Guan1, Kai Cheng1
1Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China.
Tumor immune checkpoint therapy (ICT) aims to block immune escape signals between tumor and immune cells. However, low delivery efficiency of immune checkpoint inhibitors (ICIs), narrow single-target approach, and reduced responsiveness notably hinder clinical development of ICT. Here, we developed a nanoliposome-bacteria hybrid system that acts as an antibody (Ab) factory, enabling precise tumor targeting and macrophage activation in hypoxic environments. We reprogrammed attenuated Escherichia coli MG1655 to synthesize CD47 antibodies (aCD47) in response to hypoxic tumor microenvironments while surface conjugating with redox-responsive macrophage colony-stimulating factor-loaded liposomes. This system leverages bacterial tropism to enhance macrophage infiltration and polarization. The low oxygen levels trigger in situ aCD47 expression, blocking the "do not eat me" signal and boosting macrophage antitumor activity. In addition, macrophage antigen presentation activates CD8+CD3+ T cells, amplifying systemic antitumor immunity. Analysis of the gut microbiome shows reduced pathogenicity and improved intestinal tolerance with increased probiotics.
Tumor immune checkpoint therapy (ICT) aims to block immune escape signals between tumor and immune cells. However, low delivery efficiency of immune checkpoint inhibitors (ICIs), narrow single-target approach, and reduced responsiveness notably hinder clinical development of ICT. Here, we developed a nanoliposome-bacteria hybrid system that acts as an antibody (Ab) factory, enabling precise tumor targeting and macrophage activation in hypoxic environments. We reprogrammed attenuated Escherichia coli MG1655 to synthesize CD47 antibodies (aCD47) in response to hypoxic tumor microenvironments while surface conjugating with redox-responsive macrophage colony-stimulating factor-loaded liposomes. This system leverages bacterial tropism to enhance macrophage infiltration and polarization. The low oxygen levels trigger in situ aCD47 expression, blocking the "do not eat me" signal and boosting macrophage antitumor activity. In addition, macrophage antigen presentation activates CD8+CD3+ T cells, amplifying systemic antitumor immunity. Analysis of the gut microbiome shows reduced pathogenicity and improved intestinal tolerance with increased probiotics.
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