Tudor domain-containing protein 9-targeting siRNA nanoparticles alleviate Pseudomonas aeruginosa lung injury in preclinical models by promoting neutrophil cuproptosis.

Summary

An HA-coated peptide nanoparticle delivered siRNA targeting TDRD9 to neutrophils, enhancing cuproptosis, reducing neutrophil accumulation, and ameliorating lung inflammation and edema in Pseudomonas aeruginosa pneumonia models. Mechanistically, TDRD9 inhibited neutrophil cuproptosis via PD-L1/CD80-mediated p38 MAPK signaling; nanoparticle-mediated TDRD9 silencing reversed this and reduced bacterial growth and inflammation in human lung organoids.

Key Findings

• HA-si-TDRD9 nanoparticles targeted neutrophils and reduced lung inflammation and edema in mouse P. aeruginosa pneumonia.
• TDRD9 suppresses neutrophil cuproptosis via PD-L1/CD80-mediated activation of p38 MAPK; silencing TDRD9 enhances cuproptosis.
• In human lung organoids, HA-si-TDRD9 reduced bacterial growth, apoptosis, and inflammatory responses.

Clinical Implications

Suggests a new host-directed therapy for multidrug-resistant P. aeruginosa pneumonia by enhancing neutrophil cuproptosis; requires safety, dosing, and efficacy evaluation in early-phase clinical trials.

Limitations

• Preclinical study; human clinical safety and efficacy are untested.
• Specificity to P. aeruginosa and potential off-target effects of inducing cuproptosis require careful evaluation.

Future Directions

Conduct GLP toxicology, pharmacokinetics, and first-in-human dose-escalation studies; assess efficacy against MDR strains and in comorbid models; explore combination with antibiotics.