HA/CD44–SS31 Mitochondrial Targeting of Manganese Oxide Nanozymes for Ischemia-Reperfusion-Induced Acute Kidney Injury Therapy

Ischemia-reperfusion injury is a key driver of acute kidney injury, characterized by mitochondrial reactive oxygen species (mtROS) generation. However, the lack of targeted mitochondrial scavenging mechanisms exacerbates the deleterious effects of mtROS. Here, we report the development of a mitochondria-targeted hollow mesoporous manganese oxide nanozyme, cofunctionalized with hyaluronic acid and the mitochondria-targeting peptide SS31 (HMN@HA-SS31), to enhance the catalytic activity within kidney proximal tubular epithelial cells (PTECs) and their mitochondria. HMN@HA-SS31 was synthesized through templated shell growth and orthogonal ligations, resulting in broad multi-ROS scavenging capabilities with superoxide dismutase (SOD)- and catalase (CAT)-like activities, as well as preferential mitochondrial localization. In H 2 O 2 -challenged human kidney (HK-2) cells, HMN@HA-SS31 reduced mtROS, restored membrane potential and network integrity, and significantly decreased apoptosis. In a murine I/R-AKI model, HMN@HA-SS31 traversed the compromised filtration barrier, accumulated in damaged PTECs, reduced renal ROS, improved kidney function and histopathology, inhibited the cGAS-STING pathway, limited fibrosis under a multidose regimen, and increased 21-day survival to 80% without detectable toxicity. These findings suggest that mitochondrial targeted enables localized catalysis within mitochondrial microdomains, thereby disrupting the mtROS-inflammation cycle in I/R-AKI. This study introduces a mitochondrial targeted antioxidant strategy, providing insights into the development of therapeutics for I/R-AKI.