A DPEP1-Binding and mitochondria-targeted nanocomposite relieves acute respiratory distress syndrome by inhibiting Drp1-mediated mitochondria fission.

Abstract

Acute respiratory distress syndrome (ARDS), a severe condition associated with high mortality, is characterized by uncontrollable inflammation and oxidative stress linked to mitochondrial dysfunction. Dynamin-related protein 1 (Drp1) drives pathological mitochondrial fission in patients with ARDS, leading to a sustained inflammatory response and excessive mitochondrial reactive oxygen species (mtROS) production. However, the specific inhibition of Drp1 in lung mitochondria remains challenging. Here, a multifunctional nanocomposite (DTP-LSA@MTC NPs) was developed by integrating the Drp1 inhibitor Mdivi-1 with a mitochondria-targeting tannic acid-cerium (TA-Ce) nanozyme network. Additionally, surface functionalization with an LSA peptide enabled specific binding to DPEP1 on the inflamed pulmonary endothelium, enhancing site-specific accumulation and competitively inhibiting neutrophil recruitment. Following intravenous administration, these nanoparticles efficiently targeted both pulmonary microvascular endothelial cells and mitochondria, suppressed the activity of the Drp1-NLRP3 inflammasome axis, and scavenged ROS, ultimately preventing the development of cytokine storms in preclinical models of ARDS. This targeted nanotherapeutic strategy offers a potent and translatable approach for treating ARDS and related inflammatory disorders.