A pathogen peptidoglycan scaffold coated with artificial biomembrane promotes broad resistance to bacterial infections by dynamically reprogramming macrophage metabolism.

The increasing severity of multidrug-resistant (MDR) bacteria and the shortage of effective treatment strategies urgently require the development of new immunotherapies to combat superbug infections. Trained immunity may offer a novel and effective mechanism to combat resistant superbugs. However, there are currently few materials capable of effectively activating trained immunity, highlighting the need for new agents that provide more durable protection. In this study, we developed a bacterium-like particle (BLP) based on protein-free artificial biomembrane coating immune activator, named LM@pBLP, which features a simple and rapid preparation process, excellent biocompatibility, long-term stability, and a cost-effective advantage. LM@pBLP trains the immune system to target a broad range of pathogens, offering rapid, broad-spectrum, and long-lasting protection against MDR infections. After stimulation with LM@pBLP, it activates glutathione metabolism and amino acid metabolism, induces macrophage metabolic and epigenetic reprogramming changes, and regulates phagocytosis and inflammatory responses to infection. Additionally, LM@pBLP regulates reactive oxygen species (ROS), thereby maintaining oxidative stress homeostasis. Our study demonstrates that LM@pBLP primarily provides rapid, broad-spectrum, and long-lasting protection for experimental animals by activating trained immunity, which opens a new avenue for addressing MDR infections.