Megalin-targeted Mg-Fe cyanometallate framework nanozymes calibrate mitochondrial iron-calcium homeostasis to treat acute kidney injury.

Intracellular metal ion homeostasis, particularly the precise regulation of mitochondrial iron and calcium, is essential for maintaining energy metabolism and cell survival. Once disrupted, iron-mediated oxidative reactions and calcium overload mutually amplify, rapidly leading to mitochondrial dysfunction and cellular injury. In acute kidney injury (AKI), this mitochondria-centered iron-calcium imbalance represents a critical pathological axis driving oxidative stress, programmed cell death, and inflammation. However, effective therapies that coordinately regulate both processes are not yet available. Herein, we developed a polyvinylpyrrolidone (PVP)-coated Mg-Fe cyanometallate framework nanozyme (MFC) to calibrate iron-calcium homeostasis in AKI. The PVP coating facilitates its interaction with the highly expressed Megalin receptor in renal proximal tubular epithelial cells, promoting receptor-dependent endocytosis and tubular-targeted delivery. Built on a Prussian blue-like coordination framework, MFC efficiently captures bioactive iron to suppress oxidative stress, while its ion-exchange process concurrently releases Mg2+, acting as a physiological calcium antagonist that regulates mitochondrial calcium homeostasis. By stabilizing mitochondrial structure and function, this strategy suppresses the cascade amplification of cell death and inflammatory signaling, significantly ameliorating renal injury in AKI. This study proposes a therapeutic approach for AKI by rewiring mitochondrial iron-calcium imbalance and offers a design paradigm for multifactorially coupled diseases.