Peptide–Gold Nanoparticle Hybrids as Promising Anti‐Inflammatory Nanotherapeutics for Acute Lung Injury: In Vivo Efficacy, Biodistribution, and Clearance

Gold nanoparticles (GNPs) have shown great promises in various biomedical applications. Although GNPs exhibit excellent therapeutic efficacy in in vitro and in vivo in numerous studies, there still exists significant biosafety concerns, mainly for their nonbiodegradability and tendency to be trapped in the liver and spleen. To tackle this problem, hexapeptides are utilized to modify the GNP surface to not only impart them with potent anti‐inflammatory activity, but also facilitate their rapid clearance in vivo. Previously, a unique class of peptide‐GNP hybrids that potently inhibit multiple TLR signaling pathways in macrophages was identified; in this work, it is further demonstrated that these hybrids, after intratracheal instillation, are capable of effectively reducing lung inflammation and injury by decreasing neutrophil infiltration and increasing the number of regulatory T cells in the lung in a lipopolysaccharide‐induced acute lung injury (ALI) mouse model. More importantly, these hybrids can be effectively excreted 26 h post‐administration with only 8.49 ± 0.70% of them remaining in the body, primarily in the lung and intestine and less than 0.03% accumulated in the liver and spleen. This work provides strong evidences that properly designed peptide‐GNP hybrids can serve as the next generation of effective and safe anti‐inflammatory nanotherapeutics to treat ALI. A peptide–gold nanoparticle (GNP) hybrid targets pulmonary phagocytic immune cells to reduce lung inflammation in a lipopolyscharride‐induced acute lung injury model through inhibiting TLR4 signaling, decreasing the neutrophil infiltration, and increasing the number of regulatory T cells. The hybrid can then be fast and effectively excreted within 24 h with