Nanostructured organic sheets sequestering small extracellular vesicles and reactive species to protect against radiation-induced mucositis

Abstract

Radiation-induced mucositis significantly reduces quality of life in patients undergoing radiotherapy and chemoradiotherapy for head and neck cancer. Radiation exposure increases the secretion of small extracellular vesicles carrying double-stranded DNA, which triggers excessive inflammation. To address this, we develop functionalized organic nanosheets designed to capture these inflammatory vesicles from damaged tissue. Using template-based synthesis, we create nanostructured organic sheets functionalized with CD63 aptamers, enabling selective targeting of extracellular vesicles involved in mucositis. These nanosheets show enhanced vesicle-binding capacity compared to spherical nanoparticles, efficiently suppressing inflammation by inhibiting the stimulator of interferon genes activation in macrophages. Additionally, they effectively scavenge reactive oxygen and nitrogen species, further alleviating mucosal inflammation. Flow cytometry and transcriptome analyses in irradiated animal models confirm significant mucositis mitigation. This therapeutic platform provides a promising anti-inflammatory strategy by demonstrating how biomaterial geometry and surface functionalization can modulate small extracellular vesicle-mediated inflammation in radiation-induced mucositis.