Bacteriophage immunotherapy with artificial antigen-directed immune labeling against bacterial infection

Bacteriophage therapy has been recognized as a promising anti-infection alternative, while its clinical therapeutic outcomes are compromised due to the development of bacterial resistance, ongoing host immune dysfunction at infection sites, and their failure to adequately revitalize host immunity. Here, we present a strategy for artificial antigen-directed immune labeling of bacteria, capitalizing on residual bacteriophage capsids on bacterial surfaces, which enable immune cells to achieve quicker bacterial recognition and clearance. Specifically, Mn²⁺@Man-phage anchored on bacterial surfaces and provided artificial recognition sites that enabled macrophages to phagocytize via mannose receptors, accompanied by enhanced bactericidal activity triggered by manganese ions in response to an infectious microenvironment. Moreover, immune labeling-activated macrophages enhanced antigen presentation at infection sites, further boosting specific T cell-mediated adaptive immune responses and infection eradication effects. Overall, this study illustrates a scalable bacteriophage immune therapy based on precise biological labeling and targeted modulation of immune responses, bridging the natural divide between bacteriophages and host immunity.