Enzyme-Instructed Assembly of Hexapeptide Nanoantioxidants for Treatment of Radiation-Induced Skin Injury

Abstract Radiation-induced skin injury (RISI) remains a major clinical challenge in cancer radiotherapy due to uncontrolled oxidative stress and inflammation. Current clinical management of RISI relies on topical corticosteroids, which are associated with adverse effects such as skin atrophy and telangiectasias, highlighting the need for steroid-free alternatives. Herein, a hexapeptide (RRWWWY)-based nanoantioxidant is prepared via tyrosinase-instructed assembly for RISI treatment. Such nanoantioxidants effectively scavenge excess ROS, restore redox homeostasis, and suppress radiation-induced upregulation of pro-inflammatory (IL-1β, IL-6, TNF-α) and pro-apoptotic (p53, p21) genes. Western blotting analysis confirmed decreased γ-H2AX and restored Bcl-2 expression. In an RISI rat model, hexapeptide nanoantioxidant reduced lipid peroxidation, alleviated epidermal thickening and inflammatory infiltration, and preserved the dermal collagen network and hair follicles, with no obvious systemic toxicity observed under the experimental conditions. Such nanoantioxidants provide a promising strategy for protecting normal tissues during radiotherapy, and broaden the potential of bioactive peptides in managing oxidative stress-related disorders.