Intra-Bacterial Supramolecular Assembly of Peptide With RNA Activates MRI/Fluorescence Imaging and Avoids Drug Resistance

Multidrug-resistant Gram-negative bacteria present a critical challenge for both diagnosis and therapy because diagnostic and therapeutic molecules have difficulty entering Gram-negative bacteria, and these molecules can also be expelled by bacteria using efflux pumps. Here, we report a supramolecular intrabacterial assembly peptide (IAP) that enables selective bacterial internalization via siderophore-like uptake. After internalization, IAP undergoes intra-bacterial RNA-triggered transformation from monodisperse molecules to nanofibrils, which bypass efflux pumps and enhance intra-bacterial retention. The transformation from monodisperse molecules to nanofibrils enhances r 1 relaxivity of Gd magnetic resonance imaging (MRI) motif of IAP from 9.9 ± 0.2 m M − 1 ·s − 1 (monodisperse state) to 24.5 ± 1.1 m M − 1 ·s − 1 (nanofibril state), enabling activated T 1 -weighted MRI and fluorescence imaging for Gram-negative bacteria in vivo. Beyond imaging, the IAP-RNA nanofibrils inside bacteria inhibit protein synthesis, induce reactive oxygen species accumulation, and disrupt the bacterial envelope. The multiple bacterial death pathways give IAP excellent efficacy against drug-resistant Gram-negative in both pneumonia and diabetic wound infection models, and no detectable resistance after prolonged exposure. This work presents a chemically encoded supramolecular strategy for activatable imaging and therapy based on intra-bacterial supramolecular assembly.