Membrane Fusion Strategy Boosts Immune Homeostasis, Mobilizing Macrophages to Eliminate Bacteria and Accelerate Skin Regeneration in Infected Burn Wound

Abstract Immunotherapy holds promise as an alternative to antibiotics in treating burn infections. However, the inadequacy of immune response or excessive inflammation both hinder effective bacterial clearance through immunotherapy, therefore necessitating a comprehensive approach that not only enhances immunotherapy against bacteria but also maintains immune homeostasis and promotes skin regeneration. Here, a membrane fusion‐driven combination immunotherapy is reported that mobilizes macrophages to address abovementioned limitations. The core–shell structured membrane fusion‐liposomes (MFL‐Gal‐Mal/Cur) can fuse their functional phospholipid shells with macrophages and bacteria, resulting in the remodeling of targets' surfaces with the galactose‐maltotriose (Gal‐Mal) moieties, and delivering their cores (curcumin‐loaded mesoporous polydopamine, MPDA/Cur) into targets. The embedded Gal‐Mal on membranes enhances macrophages' ability to phagocytize bacteria, as well as increases bacteria's sensitivity to immune cell‐mediated killing. The intracellular MPDA/Cur evade lysosomal degradation, exerting antibacterial effects while also enhancing macrophage lysosomal bactericidal activity through autophagy promotion. This immunotherapy enhances macrophages’ capacity to phagocytize (increase rate for S. aureus: 21%; E. coli: 29%) and eliminate intracellular bacteria (clearance rate for S. aureus: 98%; E. coli: 99%), without exacerbating inflammatory responses. The release of MFL‐Gal‐Mal/Cur from the polysaccharide composite hydrogel can alleviate pain and itching sensations in infected burns, while activating the regeneration of skin appendages.