Ferritin Nanoparticle-Mediated Sustained Delivery of Sivelestat with Poor Water Affinity Attenuates Acute Lung Injury via Dual Inhibition of NETs and Pyroptosis

Sivelestat (SV) is a commonly used drug for treating acute lung injury (ALI). Encapsulation can improve drug stability and enable controlled release, thereby potentially enhancing therapeutic outcomes. Based on this consideration, the present study utilized the reversible assembly property of ferritin (Fer) to construct SV delivery systems (Fer-SV) using ultrasound-assisted heat treatment. The optimal conditions were determined as a ferritin concentration of 2 μmol/L and a final SV mass concentration of 150 μg/mL, resulting in nanoparticles with uniform size, stable structure, and sustained-release properties. In vitro safety assessments confirmed that the system possessed good hemocompatibility and low cytotoxicity. In a mouse model of ALI induced by cecal ligation and puncture, the Fer-SV exhibited significant antioxidant and anti-inflammatory activities. It effectively reduced pulmonary oxidative stress, inhibited neutrophil infiltration and proinflammatory cytokine release, and alleviated lung injury by inhibiting the NLRP3/GSDMD pyroptosis pathway. Collectively, the findings provide compelling experimental evidence supporting the development of ferritin-based nanomedicine as an efficient and safe therapeutic approach for ALI.