A biomimetic mitochondria-targeted cerium–polyphenol nanoplatform for modulating the cGAS–STING axis in acute kidney injury

A biomimetic ultrasmall cerium–polyphenol nanoplatform (CeSAB) is developed for precision therapy of acute kidney injury. • CeSAB enables efficient renal targeting and mitochondrial accumulation via albumin-mimicking surface engineering. • The nanoplatform modulates redox homeostasis and suppresses cGAS–STING–mediated inflammatory signaling. • CeSAB disrupts mitochondrial ROS-driven pathological cascades in AKI. • Significant renal protection with excellent biosafety and in vivo clearance is achieved in multiple AKI models. Acute kidney injury (AKI) remains a major clinical challenge due to the absence of effective therapeutic interventions. Mitochondrial dysfunction in proximal tubular epithelial cells (PTECs) induces excessive reactive oxygen species (ROS) accumulation, leading to mitochondrial DNA (mtDNA) release and activation of the cGAS–STING inflammatory pathway, thereby establishing a self-amplifying cycle of oxidative stress and inflammation. Herein, we develop a biomimetic ultrasmall cerium–polyphenol nanoplatform (CeSAB) to precisely disrupt this pathogenic cascade. CeSAB is constructed through coordination-driven assembly of Ce 3+ and salvianolic acid B (SAB), integrating polyphenol-derived antioxidant activity with the dynamic redox-buffering capability of cerium. Bovine serum albumin (BSA) functionalization endows CeSAB with albumin-mimetic renal-selective delivery through megalin-mediated uptake, enabling efficient mitochondrial localization. Upon mitochondrial accumulation, CeSAB restores redox homeostasis, preserves mitochondrial integrity, and prevents mtDNA release through SAB-mediated antioxidant activity, thereby suppressing cGAS–STING activation and downstream inflammatory responses. The Ce 3+ /Ce 4+ redox cycle further reinforces oxidative microenvironment regulation, while the pH-responsive coordination structure facilitates acid inflammatory microenvironment-triggered drug release, thereby alleviating oxidative stress and tissue hypoxia. In multiple AKI models, CeSAB significantly ameliorates renal dysfunction, oxidative injury, and inflammation with excellent biosafety. This work establishes a biomimetic mitochondria-targeted nanoplatform for interrupting ROS-driven inflammatory amplification, providing a promising approach for precision treatment of AKI. Download: Download high-res image (123KB) Download: Download full-size image