Positively charged Ce-doped polypyrrole nanoparticles ameliorate acute kidney injury by endo-exogenous regulation of oxidative stress

Acute kidney injury (AKI) remains a critical clinical challenge with rapid renal function decline and limited therapeutic options. Mitochondrial reactive oxygen species (ROS)-induced oxidative stress drives AKI progression. This study develops a novel nanomedicine strategy utilizing cerium-doped polypyrrole (CePPy) nanoparticles to target ischemia-reperfusion injury-induced AKI. Synthesized via a green, one-step method, CePPy shows broad-spectrum antioxidant properties, and its positive surface charge enhances renal uptake and therapeutic efficacy compared to negatively charged counterparts. We demonstrate that positively charged CePPy (designated (+)CePPy), preferentially accumulates in the mitochondria of injured proximal tubular epithelial cells (PTECs) through transcytosis from peritubular capillaries. The (+)CePPy exhibits strong ROS scavenging capabilities as an exogenous antioxidant, and bolsters endogenous mitochondrial defenses via Mpv17l-dependent mechanisms, demonstrating significant protective effects in AKI models and preventing progression to chronic kidney disease. Furthermore, PTECs eliminate nearly 90% of CePPy within 14 days, indicating exceptional clearance efficiency. These findings highlight the potential of (+)CePPy as a promising therapeutic strategy for AKI, with significant implications for clinical translation.