Mitochondria-Targeted Metal Polyphenol Networks Inhibit Crystalline Nephropathy by Modulating SerpinE1 and Remodeling the Pathological Mineralization Microenvironment.

Crystalline nephropathy is driven by a self-perpetuating cycle in which crystal-induced tubular injury promotes further nucleation, growth, and aggregation, transforming the kidney into a pathological mineralization niche. Conventional therapies fail to disrupt this vicious loop, while nanomedicines are hindered by the glomerular filtration barrier (<10 nm), and natural antioxidants like protocatechuic acid (PCA) suffer from poor bioavailability. Here, we report a 7.3 nm mitochondria-targeted metal-polyphenol network (Fe-PCA@TPP) that overcomes both delivery and targeting challenges to directly intervene at sites of redox imbalance. Formed via PCA-Fe3+ coordination and functionalized with triphenylphosphonium (TPP), Fe-PCA@TPP efficiently traverses the glomerular barrier, accumulates selectively in mitochondria, scavenges free radicals broadly, restores redox homeostasis, and potently inhibits calcium oxalate (CaOx) crystal nucleation, growth, and aggregation. In vitro, Fe-PCA@TPP protects renal tubular epithelial cells from oxalate-induced oxidative stress by preserving mitochondrial bioenergetics and preventing apoptosis. In vivo, it preferentially accumulates in the kidney, reduces CaOx deposition, improves renal function, and downregulates markers of injury and inflammation. Mechanistically, Fe-PCA@TPP targets Plasminogen Activator Inhibitor Type 1 (SerpinE1) to block oxidative stress-apoptosis cascades, thereby remodeling the intrarenal pathological microenvironment. This work presents a size-compatible, mitochondria-targeted, and SerpinE1-specific nanoplatform that integrates crystal inhibition, redox regulation, and efficient renal clearance, offering a promising therapeutic strategy for crystalline nephropathy.