A Precision-Guided “Trojan Horse” for Tissue-Cell-Bacteria Targeted Therapy of Salmonella Intestinal Infections

Salmonella enterica infections, characterized by strong invasiveness, are prone to causing serious systemic transmission, posing a significant threat to public health. This study proposes a “Trojan horse“ strategy for oral treatment of Salmonella infection utilizing a “micro-nano composite” platform with intestinal microenvironment responsiveness, host cell targeting, and bacterial membrane fusion characteristics. The oral composite microspheres release silicasomes in response to elevated matrix metalloproteinase-9 (MMP9) levels at infected intestinal sites. The released silicasomes adhere to the intestinal mucus layer, prolonging retention time, and are subsequently internalized into epithelial and macrophage cells via the SR-B1 receptor. Crucially, the membrane fusion lipid layer of the silicasomes fused with the intracellular Salmonella membrane, thereby overcoming the outer membrane barrier of the Gram-negative bacteria. In vivo and in vitro results showed that this process broadened the antibacterial activity of linezolid against Salmonella by more than 16-fold, achieving an intracellular bacterial clearance rate of 85–95%. Moreover, this system repaired intestinal barrier by increasing TJ protein expression by over 70% and reducing inflammatory cytokine levels by more than 80%. Summarily, this ″micro-nano composite″ platform eradicated Salmonella following a sequential tissue-cell-bacteria order, restored gut microbiota balance, and prevented systemic dissemination, offering a promising solution for intestinal infections.