An Inhalable Spike–Conjugated Gold Nanoparticle for Treating Acute Lung Inflammation

Abstract Acute respiratory distress syndrome (ARDS) is a severe lung inflammatory condition with a global mortality rate of ≈40%. Yet, many treatments are invasive and non‐specific for ARDS, require days to yield efficacy, or suffer from systemic side effects and limited delivery to the lung epithelium, a key protective structure against ARDS. A disease‐driven, non‐invasive nanomedicine is reported for ARDS. Initially, the transient, sequential activation of L–SIGN and ACE2 receptors on the lung epithelium induced by ARDS onset in two hamster models (lipopolysaccharides and hydrochloric acid induction) is discovered. With this bioinspiration, an inhalable, Spike receptor–binding domain–conjugated gold nanoparticle is designed for tissue‐wide delivery to ARDS lungs, with its specific entry to epithelial cells mediated additively by both receptors. The gold core naturally blocks p38α mitogen‐activated protein kinase and polo‐like kinase 3 without chemical or biological drugs. Notably, this nanoparticle reduces lung inflammation, oxidative stress, and tissue injury more effectively than steroid after six total hours of inhalation, improves lung function, and does not lead to systemic retention or toxicity 1–year post–treatment. Inhalable, epithelium–targeting nanomedicines may offer safe and effective treatments for lung diseases.