Lipopolysaccharide‐Triggered Self‐Assembling Peptide Nanotraps for Coordinated Capture‐Killing‐Endotoxin Neutralization in Complicated Urinary Tract Infection

ABSTRACT Complicated urinary tract infections (cUTIs) caused by uropathogenic E. coli (UPEC) remain difficult to treat because multidrug resistance and continuous urinary washout jointly limit antibacterial efficacy and local drug retention. Here, a lipopolysaccharide (LPS)‐responsive supramolecular peptide conjugate, PpIX‐GFFVLK‐HWKAVNWLKPWT (PFFH), is developed to address this delivery–retention trade‐off through pathogen‐triggered structural adaptation. PFFH integrates an E. coli LPS‐binding motif, a β‐sheet‐forming self‐assembly segment, and a PpIX sonosensitizer. It remains dispersed during delivery but transforms into peribacterial nanofibrous networks upon LPS recognition, promoting bacterial trapping and positioning PpIX near the bacterial interface for localized sonodynamic ROS activity. PFFH retains LPS‐responsive assembly and antibacterial activity under urine‐mimicking conditions and effectively kills reference and multidrug‐resistant UPEC. The same LPS‐binding motif also sequesters bacteriolysis‐derived endotoxin and attenuates inflammatory activation. In a mouse cUTI model, PFFH shows prolonged retention at infected urinary sites, reduces bacterial burdens, and alleviates inflammatory injury. Thus, PFFH extends LPS‐triggered structural adaptation beyond bacterial trapping to resolve the delivery–retention trade‐off in cUTIs, while coupling peribacterial sonodynamic activity with endotoxin regulation in a single molecular platform, thereby establishing a disease‐adapted supramolecular strategy for drug‐resistant cUTIs.