Charge-dependent mitochondrial targeting of cerium-doped polypyrrole nanoparticles to injured renal tubules for acute kidney injury therapy

Acute kidney injury (AKI) is a critical medical condition with limited treatment options and frequently progresses to chronic kidney disease (CKD). This study introduces a novel nanotherapeutic approach based on positively charged cerium-doped polypyrrole nanoparticles [(+)CePPy] for AKI treatment. The positive surface charge of these nanoparticles enhances their cellular uptake and mitochondrial targeting in proximal tubular epithelial cells (PTECs), which play a central role in the pathophysiology of AKI. Comprehensive in vitro and in vivo evaluations demonstrate that (+)CePPy effectively scavenges reactive oxygen species (ROS), ameliorates mitochondrial dysfunction, attenuates apoptosis, and prevents AKI-to-CKD progression. The nanoparticles exhibit excellent biocompatibility and undergo efficient renal clearance within 14 days. Mechanistically, the renoprotective effects involve both direct elimination of ROS and the reinforcement of endogenous antioxidant defenses through upregulation of the Mpv17 mitochondrial membrane protein-like (Mpv17l) pathway. Furthermore, we report that early endosome antigen 1 (EEA1) upregulation mediates the enhanced renal targeting of (+)CePPy under AKI conditions. This research highlights the potential of charge-modulated nanotherapeutics as a translatable strategy for renal protection and presents a promising approach for AKI treatment.