Nanostructured Organic Sheets Shield Against Radiation-induced Mucositis by Sequestering Small Extracellular Vesicles and Reactive Species

Radiation-induced mucositis (RIM) is a major complication of radiotherapy (RT) and chemoradiotherapy (CRT), significantly reducing the quality of life for patients with head and neck cancer. Radiation-induced mucosa injury has been demonstrated to enhance the biogenesis and secretion of small extracellular vesicles (sEVs), with their double-stranded DNA (dsDNA) cargo activating excessive pro-inflammatory signaling cascades. To address this, we developed functionalized organic nanosheets capable of sequestering radiation-induced sEVs from affected tissues as a novel therapeutic approach for RIM mitigation. Utilizing template-based synthesis methodology, we engineered organic sheet-like nanoplatforms through controlled degradation of MoS2 templates to produce CD63 aptamer-functionalized polyglycerol-amine (PG) nanosheets (PG-NSA) that selectively target sEVs in inflammatory mucositis. These nanosheets demonstrate a higher binding capacity to sEVs compared to PG-based nanospheres, due to their flexible and crimpable 2D backbone, resulting in more efficient suppression of stimulator of interferon genes (STING) activation in macrophages. In addition, PG-NSA also exhibits robust reactive oxygen and nitrogen species (RONS) reduction ability, which is also significant for mitigating RIM. Flow cytometry and transcriptome analysis of irradiated tissues further confirmed the alleviation of mucositis in animal models. This innovative nanoplatform serves as an effective anti-inflammatory intervention, offering a novel strategy for sEVs elimination and providing new insights into the regulatory mechanisms between inflammatory mediators and biomaterials in mucositis.