A DPEP1-Binding and Mitochondria-Targeted Nanocomposite Relieves Acute Respiratory Distress Syndrome by Inhibiting Drp1-mediated Mitochondria Fission

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.