Selective Organ‐Targeting Hafnium Oxide Nanoparticles with Multienzyme‐Mimetic Activities Attenuate Radiation‐Induced Tissue Damage

Abstract Radioprotective agents hold clinical promises to counteract off‐target adverse effects of radiation and benefit radiotherapeutic outcomes, yet the inability to control drug transport in human organs poses a leading limitation. Based upon a validated rank‐based multigene signature model, radiosensitivity indices are evaluated of diverse normal organs as a genomic predictor of radiation susceptibility. Selective ORgan‐Targeting (SORT) hafnium oxide nanoparticles (HfO₂ NPs) are rationally designed via modulated synthesis by α‐lactalbumin, homing to top vulnerable organs. HfO₂ NPs like Hensify are commonly radioenhancers, but SORT HfO₂ NPs exhibit surprising radioprotective effects dictated by unfolded ligands and Hf(0)/Hf(IV) redox couples. Still, the X‐ray attenuation patterns allow radiological confirmation in target organs by dual‐beam spectral computed tomography. SORT HfO₂ NPs present potent antioxidant activities, catalytically scavenge reactive oxygen species, and mimic multienzyme catalytic activities. Consequently, SORT NPs rescue radiation‐induced DNA damage in mouse and rabbit models and provide survival benefits upon lethal exposures. In addition to inhibiting radiation‐induced mitochondrial apoptosis, SORT NPs impede DNA damage and inflammation by attenuating activated FoxO, Hippo, TNF, and MAPK interactive cascades. A universal methodology is proposed to reverse radioenhancers into radioprotectors. SORT radioprotective agents with image guidance are envisioned as compelling in personalized shielding from radiation deposition.