“Trojan Horse” Delivery of Gallium Nanodroplets As Intelligent Ferroptosis Inhibitors for Targeted Acute Kidney Injury Therapy

Ferroptosis, driven by iron overload and lipid peroxidation, is a key contributor to acute kidney injury (AKI), yet current iron-chelation therapies often disrupt systemic iron homeostasis. Here, we present a novel “competitive uptake” strategy utilizing gallium nanodroplets (Ga NDs) that employ a Trojan-horse-like mechanism to selectively modulate iron metabolism in pathological environments. These intelligently designed Ga NDs release Ga 3+ as a functional Fe 3+ mimic, competitively binding to transferrin and effectively intercepting iron-dependent ferroptotic pathways. These intelligently responsive Ga NDs not only modulate iron metabolism but also exhibit potent antioxidant and anti-inflammatory activities. In vitro studies demonstrate that Ga NDs efficiently scavenge reactive oxygen and nitrogen species (RONS), stabilize mitochondrial membrane potential, and inhibit ferroptosis via upregulation of GPx4 and suppression of PTGS2 expression. In vivo, Ga NDs demonstrate kidney-targeted accumulation and effective mitigation of ischemia-reperfusion-induced AKI and preserve renal function without systemic toxicity. This work introduces a biocompatible and multimodal nanotherapeutic with translational potential for AKI treatment, leveraging a sophisticated Trojan horse strategy to precisely target ferroptosis in complex renal pathologies.