A Mitochondria‐Targeted and pH‐Responsive Fe 3+ –Astragalin Nanoplatform Reprograms Metabolism to Protect Against Acute Kidney Injury

ABSTRACT Acute kidney injury (AKI) is a life‐threatening clinical syndrome characterized by abrupt renal dysfunction, excessive oxidative stress, inflammatory activation, and profound metabolic disturbances, yet effective therapeutic strategies remain limited. Herein, we developed an ultrasmall pH‐responsive nanoplatform (FeAst) through the self‐assembly of Fe 3+ and the natural flavonoid Astragalin (Ast) for injury‐responsive renal delivery and metabolic intervention. The Fe 3+ –phenolic coordination network endows FeAst with excellent biocompatibility, intrinsic reactive oxygen species (ROS)‐scavenging capacity, and mitochondria‐targeting capability. Importantly, FeAst preferentially accumulated in injured kidneys, enabling targeted renal delivery. Moreover, the mildly acidic microenvironment associated with AKI triggered partial dissociation of the coordination network, enabling localized Ast release and sustained therapeutic activity. Across multiple experimental models of kidney injury, FeAst markedly improved renal function, alleviated tubular injury, suppressed inflammatory responses, and restored redox homeostasis. Mechanistically, FeAst preserved mitochondrial integrity, re‐established glutathione‐dependent antioxidant defense, suppressed ferroptosis‐related processes by reducing lipid peroxidation and restoring ferroptosis defense systems, and reprogrammed TCA cycle‐associated energy metabolism. Moreover, FeAst activated PPAR signaling and suppressed p38 MAPK/NF‐κB‐mediated inflammatory responses, thereby enhancing cellular bioenergetics and resistance to oxidative stress. Collectively, this injury‐responsive nanoplatform integrates selective renal accumulation, controlled drug release, and metabolic reprogramming to provide a promising strategy for precision kidney injury therapy.