Hybrid Cell Membrane‐Engineered Nanocarrier for Triple‐Action Strategy to Address <i>Pseudomonas aeruginosa</i> Infection

Bacterial infections resistant to antimicrobial treatments, particularly those caused by Pseudomonas aeruginosa (P. aeruginosa), frequently lead to elevated mortality rates. Tackling this resistance using therapeutic combinations with varied mechanisms has shown considerable promise. In this study, a bioinspired nanocarrier is successfully designed and engineered for targeted antibiotic delivery and toxin/bacteria clearance. This is achieved by encapsulating antibiotic-loaded framework nucleic acids with hybrid cell membranes acquired from neutrophils and platelets. By coating the hybrid membrane outside the shell, nanocarriers are endowed with the function of neutrophil-like chemotaxis and platelet-like bacteria adhesion to achieve the first stage of inflammation targeting. Based on the specific binding of bacteria toxin to the hybrid membrane, the release of antibiotic-loaded framework nucleic acids is triggered by toxin-mediated membrane lysis to fulfill the second stage of toxin neutralization and bacteria killing. Meanwhile, the immunomodulation potential of framework nucleic acids enables nanocarriers to accomplish the third stage of reversing the immunosuppressive microenvironment. In mouse models of acute and chronic P. aeruginosa pneumonia, the nanocarriers can reduce bacterial burden at a low dosage and decrease mortality with negligible toxicity. In sum, these findings have illustrated the remarkable capability of nanocarriers in treating recalcitrant bacterial infections.