Precision PEGylation of ZnO quantum dots enables selective intracellular killing of Uropathogenic E. coli via multimodal antibacterial mechanisms without inducing resistance.

The intracellular persistence and biofilm-forming capacity of uropathogenic (UPEC) are major contributors to urinary tract infections (UTIs) recurrence and antibiotic failure. Here, we report a precisely engineered nanotherapeutic based on ZnO quantum dots (QDs) surface-functionalized with low-molecular-weight polyethylene glycol (PEG200), designed to enhance biocompatibility while preserving potent antibacterial activity. The optimized ZnO@PEG200 QDs exhibited excellent aqueous dispersibility, minimal cytotoxicity, and broad-spectrum efficacy against both drug-sensitive and multidrug-resistant strains. Mechanistic studies revealed that the QDs exerted multimodal bactericidal effects, including Zn ion release, membrane destabilization, intracellular reactive oxygen species (ROS) generation, genomic DNA fragmentation, and transcriptional repression of key virulence genes such as papG, FimH, and FliC. Notably, ZnO@PEG200 QDs disrupted bacterial motility and eradicated established biofilms even at sub-inhibitory concentrations. Long-term passaging assays demonstrated that sub-MIC exposure to ZnO@PEG200 QDs did not induce resistance development. In vivo, the QDs preferentially accumulated in the bladder and kidneys, significantly reduced intracellular bacterial burden, suppressed inflammatory cytokine expression, and promoted tissue repair in a murine UTIs model. Collectively, this work establishes ZnO@PEG200 QDs as a safe and effective nanoplatform for precision antimicrobial therapy, offering a resistance-free strategy for the treatment of intracellular and biofilm-associated bacterial infections.