Jinpeng Li, Chen Zhou, Ming Yang, Xinggui Chen, Cui Li, Yong Sun, Hongning Wang, Changwei Lei
Intestinal Salmonella infections are primarily treated with antibiotics, yet non-selective bactericidal activity often disrupts the gut microbiota and limits therapeutic efficacy. Here, we introduce a precision anti-infective strategy based on spatial reprogramming, which redefines where antibacterial activity occurs rather than increasing antimicrobial potency. By functionally integrating Salmonella-specific nanobodies anchored on oral hydrogel microgels with meropenem-loaded bacterial membrane vesicles, we construct a targeted delivery system, termed HAMA-Nb@BM. Surface-anchored nanobodies selectively capture and concentrate dispersed Salmonella, spatially confining pathogens to the microgel surface. The microgels subsequently trigger the release of antibiotic-loaded vesicles, which deliver antibiotics directly into the periplasmic space of nearby pathogens via outer-membrane fusion, thereby avoiding diffusion-dependent dilution of free antibiotics and minimizing off-target microbiota perturbation. In a murine Salmonella infection model, this spatially confined therapy reduces intestinal pathogen burden, preserves microbiota homeostasis, and promotes inflammation resolution and mucus barrier restoration. This work establishes spatially reprogrammed antibacterial delivery as a strategy to reconcile effective pathogen clearance with host intestinal homeostasis.