Polydopamine–polyethylene glycol–liproxstatin-1 nanoparticles inhibit ferroptosis for enhanced treatment of neutrophilic asthma

Ferroptosis is an iron-dependent programmed cell death mechanism triggered by the accumulation of lipid-based reactive oxygen species (ROS). It is closely implicated in the pathogenesis of asthma. Liproxstatin-1 (LIP-1) is a ferroptosis inhibitor that is beneficial for treating neutrophilic asthma. However, low water solubility, limited blood concentration, and poor mucus permeability and biocompatibility limit the therapeutic efficacy of LIP-1. In this study, we successfully constructed polydopamine–polyethylene glycol–LIP-1 nanoparticles (PDA-PEG-LIP-1 NPs) for the treatment of neutrophilic asthma. Inhalation of PDA-PEG-LIP-1 NPs effectively inhibited lipopolysaccharide (LPS)- and interleukin (IL)-13-induced ferroptosis by alleviating lipid peroxidation and ROS production and chelating free ferrous ions (Fe 2+ ). In addition, results from asthma mouse models demonstrated that inhalation of PDA-PEG-LIP-1 NPs could overcome the limitations of LIP-1 and effectively inhibit ferroptosis. This research suggests that PDA-PEG-LIP-1 NPs are an effective, practical, and safe option for treating neutrophilic asthma.