Enzyme-responsive peptide dendron nanoassemblies for targeting and eliminating intracellular drug-resistant bacteria

Certain intracellular pathogens can reside within cells to evade host immune defenses and exhibit high tolerance to antibiotics. Current treatments for intracellular bacterial infections are limited by poor cellular penetration, inadequate targeting of infected sites, and inefficacy against drug-resistant bacteria. Here, peptide dendron nanoassemblies comprising self-assembling regions, cell-penetrating motifs, enzyme-responsive sequences, and targeting ligands are developed to eliminate intracellular drug-resistant bacteria. The peptide dendrons self-assemble into nanoparticles that bind to membrane integrins via targeting sequence. The receptor-ligand interaction triggers a structural transformation into nanofibers for prolonged retention on the membrane surfaced of infected cells. Subsequently, they transform to nanoparticles upon tailored by bacteria-secreted enzyme, facilitating cellular uptake to target and eradicate intracellular drug-resistant bacteria. Self-assembling peptide dendrons further enhance macrophage resistance to infection-induced damage by modulating ferroptosis. The in vivo efficacy of peptide dendron nanoassemblies in removing intracellular drug-resistant bacteria is demonstrated in male mice and piglet infection models. This study provides a promising therapeutic strategy for treating intracellular drug-resistant infections. Intracellular bacterial infections remain difficult to treat. Here, the authors report enzyme-responsive peptide dendron nanoassemblies with size-transforming capabilities that target and eradicate intracellular drug-resistant bacteria while protecting macrophages from damage caused by intracellular bacterial infection.