pH/enzyme dual-responsive nanoparticles hitchhike neutrophils to enhance bacteria-induced acute lung infection treatment

Acute lung infection (ALI) represents a major global health challenge with high morbidity and mortality. The current clinical approach primarily relies on antibiotic therapy, yet the therapeutic efficacy is severely limited by poor drug targeted delivery. Here, we developed neutrophil-hijacking pH/enzyme dual-responsive rifampicin-loaded nanoparticles (RFP‑NENPs) composed of pH-sensitive polymer (mPEG_2K-PAE) and enzyme-responsive polymer PCL-PEG_2K decorated with neutrophil elastase-targeting peptide, which can self-assemble into nanoparticles. After intravenous injection, the RFP‑NENPs can specifically target and hijack neutrophils in vivo, and deposit at the infectious site due to inflammatory chemotaxis of pro-inflammatory neutrophils via the immune response, followed by releasing the cargos due to the low pH and bacterial enzymes in the infectious microenvironment. In a mouse model of acute lung infection by Staphylococcus aureus, RFP‑NENPs effectively cleared the bacteria and caused no detectable systemic toxicity. This work not only presents an effective therapeutic for enhanced acute lung infection treatment, but also offers a neutrophil-mediated drug delivery strategy.