Engineered immune cells help eliminate severe bacterial infections effectively

Severe bacterial infections remain a major global health challenge because antibiotics alone often fail when the host immune system becomes dysfunctional. During advanced infections, macrophages-the body's professional pathogen-clearing cells-frequently lose their ability to efficiently recognize, engulf and destroy invading bacteria. Restoring these immune functions has become an important goal for next-generation anti-infective therapies.

A research team led by investigators from Nankai University and the First Affiliated Hospital of Wenzhou Medical University has now developed a programmable macrophage interface engineering strategy that rapidly converts ordinary macrophages into pathogen-targeting immune cells capable of efficiently eliminating bacteria even under immunosuppressive conditions. Their findings were recently published in Science Bulletin.

Unlike conventional immune cell engineering approaches that rely on genetic modification, the new strategy remodels only the cell membrane. The researchers designed membrane-fusogenic liposomes carrying bacteriophage-derived receptor-binding proteins (RBPs) together with intracellular antibiotics. Following membrane fusion, the RBPs become anchored on the macrophage surface, allowing the engineered cells to specifically recognize target bacteria, while the antibiotic payload is simultaneously delivered into the macrophage cytoplasm.

"This approach transforms macrophages into programmable antibacterial cells without altering their genome," the researchers explained. "The engineering process is rapid, modular and preserves the cells' native biological properties."

To understand why such engineering is needed, the researchers first analyzed publicly available single-cell transcriptomic datasets from multiple human infectious diseases. They found that macrophages from diverse infected tissues consistently exhibited a hypofunctional state characterized by impaired pathogen recognition, reduced phagocytic activity and weakened immune coordination. These findings suggest that immune dysfunction is a common barrier limiting the effectiveness of conventional antimicrobial therapies.

The engineered macrophages successfully overcame these limitations. Bio-atomic force microscopy and quartz crystal microbalance analyses demonstrated significantly strengthened mechanical interactions between engineered macrophages and their target bacteria. These reinforced cell-bacteria interfaces greatly improved bacterial adhesion, immobilization and subsequent internalization.

Live-cell imaging further showed that the engineered macrophages efficiently trapped bacteria and dramatically reduced bacterial motility before engulfment. The platform achieved highly specific recognition of both Klebsiella pneumoniae and Staphylococcus aureus by simply exchanging the bacteriophage-derived receptor proteins, demonstrating the modularity of the system.

In mouse models of bacterial pneumonia and bacterial meningitis, treatment with engineered macrophages markedly reduced bacterial burden, alleviated inflammatory injury and significantly improved organ function. The therapeutic cells not only eliminated pathogens but also remodeled the immune microenvironment by reducing excessive inflammatory macrophages, promoting tissue-repair-associated macrophages and restoring immune homeostasis.

Single-cell RNA sequencing further revealed that the therapy reversed infection-associated immune dysfunction by restoring macrophage antigen presentation, improving immune cell communication and reducing T-cell exhaustion, thereby coordinating both innate and adaptive immune responses during infection resolution.

Importantly, the researchers observed favorable short-term biosafety. The engineered macrophages showed minimal immunogenicity following repeated administration, and no significant liver, kidney or hematological toxicity was detected in treated animals.

Because the platform is based on membrane interface engineering rather than permanent genetic modification, it offers several potential translational advantages, including rapid preparation, modular pathogen specificity and reduced biosafety concerns. Different bacteriophage receptor-binding proteins can be incorporated to target different bacterial species without redesigning the overall engineering platform.

The researchers believe that this programmable immune-cell engineering strategy could provide a versatile platform for treating severe bacterial infections, particularly those associated with immune suppression, intracellular pathogens or infections occurring in difficult-to-access organs such as the lung and brain.