Programmable macrophage interface engineering enables targeted antibacterial therapy in immunosuppressed infections.

Severe bacterial infections remain difficult to treat due to both antimicrobial resistance and infection-induced immune dysfunction, which together limit pathogen clearance. Here, we report a non-genetic immune cell engineering strategy that increases antibacterial activity by reprogramming macrophage interfaces. Integrated analysis of clinical single-cell transcriptomic datasets from diverse infections revealed a conserved hypofunctional macrophage state characterized by impaired phagocytosis, lysosomal activity, and immune coordination. To bypass this dysfunction, we engineered macrophages using membrane-fusogenic liposomes functionalized with bacteriophage-derived receptor-binding proteins and loaded with intracellular antibiotics. This approach enables programmable, pathogen-specific recognition while delivering antimicrobial payloads within macrophages. Engineered macrophages exhibited enhanced bacterial capture, immobilization, and intracellular killing, maintaining efficacy under immunosuppressive conditions. In mouse models of Klebsiella pneumoniae pneumonia and Staphylococcus aureus meningitis, treatment resulted in near-complete pathogen clearance, reduced inflammation, and restoration of organ function. Single-cell analyses further showed reversal of immune dysfunction and reestablishment of coordinated innate and adaptive immune responses. These findings establish macrophage interface engineering as a strategy to overcome immune dysfunction and enable targeted antibacterial therapy, providing a potential platform for treating severe infections.