Severe bacterial infections can overwhelm the immune system even when effective antibiotics are available. In advanced disease, macrophages—the immune cells responsible for detecting, engulfing and destroying invading microbes—may enter a hypofunctional state. Their ability to recognize pathogens, attach to them and coordinate with other immune cells becomes impaired, allowing bacteria to persist while inflammation continues to damage vital tissues. A research team from Nankai University and the First Affiliated Hospital of Wenzhou Medical University has developed a programmable strategy designed to restore these lost functions. Instead of permanently altering macrophage genes, the researchers temporarily remodelled the cells’ outer membranes, creating engineered immune cells that can selectively seek out and attack specific bacteria under immunosuppressive conditions.
The approach uses membrane-fusogenic liposomes, microscopic lipid vesicles engineered to merge with the macrophage membrane. These liposomes carry two functional components: bacteriophage-derived receptor-binding proteins, known as RBPs, and intracellular antibiotics. RBPs are molecular structures used by bacteriophages to recognize and attach to particular bacterial surfaces. Once the liposomes fuse with a macrophage, the RBPs become displayed on the cell membrane, effectively giving the immune cell a new molecular recognition system. At the same time, the antibiotic cargo is released inside the macrophage. The resulting cell is equipped both to identify a selected bacterial species at its surface and to deploy antimicrobial activity after engulfment, without requiring genetic modification of its nucleus.
The researchers first investigated whether macrophage dysfunction represents a recurring feature of severe infection rather than an isolated phenomenon. They analyzed publicly available single-cell transcriptomic datasets collected from patients with several infectious diseases and examined gene-expression patterns in macrophages from different tissues. Across these datasets, macrophages commonly showed reduced signatures associated with pathogen recognition, phagocytosis and immune coordination. The findings indicate that infection can push macrophages into a state in which they remain present but are less capable of performing their core defensive tasks. This impairment may help explain why antibiotic treatment alone can fail: drugs may reduce bacterial replication, but they cannot fully compensate for immune cells that struggle to locate, capture or eliminate the remaining pathogens.
After membrane interface engineering, the modified macrophages displayed stronger physical interactions with their target bacteria. The team used bio-atomic force microscopy to measure the mechanical contacts formed between individual cells and microbes, while quartz crystal microbalance analysis provided additional information about binding and mass changes at the interface. These experiments showed that the engineered receptor proteins reinforced the attachment between macrophages and bacteria. The stronger interaction helped the immune cells immobilize their targets and increased the likelihood that the bacteria would be internalized through phagocytosis. In effect, the researchers converted the macrophage surface into a selective capture system, improving the first physical step required for bacterial clearance.
Live-cell imaging revealed how the engineered cells behaved during this process. Rather than allowing bacteria to move freely around them, the modified macrophages rapidly trapped and slowed target organisms before engulfment. The system could be redirected toward different pathogens by exchanging the bacteriophage-derived RBPs incorporated into the liposomes. In experiments involving Klebsiella pneumoniae and Staphylococcus aureus, the macrophages showed specific recognition of the intended bacterial targets. This modularity is central to the platform’s design. Because the recognition element can be changed without rebuilding the entire cell-engineering procedure, the same general strategy could potentially be adapted to bacterial species with different surface structures, including pathogens that emerge or acquire antibiotic resistance.
The intracellular antibiotic component provides a second layer of defense. Once a bacterium is engulfed, it enters the macrophage within a membrane-bound compartment, where it may survive if the cell’s antimicrobial machinery is weakened. Delivering antibiotics directly into the macrophage cytoplasm is intended to increase the concentration of antimicrobial cargo near internalized bacteria and to compensate for defects in the host cell’s killing capacity. The combined mechanism therefore links external recognition with internal pathogen control: the engineered RBP helps the macrophage locate and capture the bacterium, while the intracellular antibiotic supports its destruction after uptake. The researchers describe this as a temporary, programmable reconfiguration of immune-cell function rather than a permanent genetic transformation.
The therapeutic effects were tested in mouse models of bacterial pneumonia and bacterial meningitis, two infections in which uncontrolled bacterial growth and inflammatory injury can rapidly compromise organ function. Animals treated with the engineered macrophages showed lower bacterial burdens, reduced tissue inflammation and improved indicators of organ performance compared with untreated controls. The cells appeared to contribute not only to direct bacterial removal but also to broader changes in the immune environment. Treatment reduced populations associated with excessive inflammatory activity, encouraged macrophage states linked to tissue repair and helped restore a more balanced local immune response. These findings are particularly relevant to infections in which immune overactivation and immune suppression occur simultaneously, creating a cycle of pathogen persistence and collateral tissue damage.
Single-cell RNA sequencing provided further evidence that the therapy influenced immune networks beyond the engineered macrophages themselves. Following treatment, macrophage populations showed improved expression of genes associated with antigen presentation, a process through which immune cells display pathogen-derived material to coordinate adaptive immunity. Signals involved in communication between immune-cell populations were also restored, while markers associated with T-cell exhaustion were reduced. The results suggest that engineered macrophages may act as immune organizers as well as bacterial scavengers. By improving antigen presentation and cellular communication, they could help reconnect innate and adaptive immune responses during the transition from uncontrolled infection to resolution. The researchers emphasize that this systems-level effect may be important in severe disease, where multiple immune compartments become dysfunctional at the same time.
Short-term safety studies produced encouraging results. Repeated administration of the engineered macrophages caused minimal detectable immunogenicity in the treated animals, and the researchers reported no significant liver, kidney or blood-related toxicity. The membrane-based design may offer a practical safety advantage because it does not introduce permanent genetic changes into the cells. It also allows the engineering process to be carried out rapidly and adjusted according to the bacterial target. However, the findings remain preclinical, and important questions must be answered before the technology can be evaluated in people. Researchers will need to determine how long the membrane-bound receptors remain functional, how engineered cells behave in human tissues, whether they can reach infected organs efficiently and how the platform performs against polymicrobial infections or bacteria with rapidly changing surface properties.
The study presents macrophage membrane engineering as a flexible alternative to conventional immune-cell modification. By combining bacteriophage-derived targeting molecules with intracellular antibiotics, the platform addresses two major barriers in severe infection: inadequate pathogen recognition and ineffective intracellular killing. Its proposed applications include infections associated with immune suppression, intracellular bacterial disease and difficult-to-access sites such as the lungs and brain. The approach could also be adapted as new receptor-binding proteins are identified, potentially creating a library of pathogen-specific immune-cell products. While further studies are needed to establish durability, large-scale manufacturing and long-term safety, the work suggests that temporarily reprogrammed macrophages could become a new class of anti-infective therapy—one that does not simply deliver another antibiotic, but actively rebuilds the host’s capacity to find, capture and eliminate dangerous bacteria.
Subject of Research: Programmable membrane engineering of macrophages for targeted antibacterial therapy
Web References: https://doi.org/10.1016/j.scib.2026.07.008
References: Science Bulletin, DOI: 10.1016/j.scib.2026.07.008
Image Credits: © Science Bulletin
Keywords
macrophages, bacterial infections, immune-cell engineering, bacteriophage receptor-binding proteins, membrane-fusogenic liposomes, intracellular antibiotics, Klebsiella pneumoniae, Staphylococcus aureus, bacterial pneumonia, bacterial meningitis, single-cell RNA sequencing, antimicrobial therapy
