Engineered Mammalian Cell Membrane‐Coated Nanoparticles for Targeted Delivery of Antibiotics to Eradicate Drug‐Resistant Gram‐Negative Bacteria

ABSTRACT The increasing prevalence of drug‐resistant bacteria poses a major global health threat. The outer membrane of Gram‐negative bacteria acts as a natural barrier that limits the penetration of antimicrobial agents, reducing therapeutic efficacy. To overcome the outer membrane barrier, we developed a biomimetic antibiotic‐delivery system composed of ampicillin‐loaded mesoporous polydopamine (MPDA) nanoparticles coated with TLR4‐overexpressing cell membranes (MPDA‐Amp‐cmTLR4). The engineered membrane promoted LPS‐sensitive association with Gram‐negative bacteria and concentrated the nanoparticles at the bacterial envelope. The targeted MPDA‐Amp‐cmTLR4 nanoparticles substantially reduced the required Amp concentration and markedly inhibited drug‐resistant Escherichia coli , whereas matched non‐targeted formulations showed limited activity. NIR‐induced photothermal heating provided an additional enhancement in the externally accessible wound model by accelerating local drug release and increasing bacterial stress. Proteomic and biochemical analyses indicated that the treatment disrupted cell‐wall and membrane homeostasis and induced an oxidative‐stress response. In murine models, MPDA‐Amp‐cmTLR4 accumulated at infected lungs, reduced systemic bacterial burdens and inflammatory responses in sepsis, and promoted the healing of infected wounds. This biomimetic strategy therefore enhances the local efficacy of antibiotics against drug‐resistant Gram‐negative bacteria while reducing the required bulk antibiotic concentration.