Multifunctional Graphdiyne-Cerium Oxide Nanozymes Facilitate MicroRNA Delivery and Attenuate Tumor Hypoxia for Highly Efficient Radiotherapy of Esophageal Cancer

Radioresistance is an important challenge for clinical treatments. The main causes of radioresistance include hypoxia in the tumor microenvironment, the antioxidant system within cancer cells, and the upregulation of DNA repair proteins. Here, a multiple radiosensitization strategy of high-Z-element-based radiation enhancement is designed, attenuating hypoxia and microRNA therapy. The novel 2D graphdiyne (GDY) can firmly anchor and disperse CeO nanoparticles to form GDY-CeO nanocomposites, which exhibit superior catalase-mimic activity in decomposing H O to O to significantly alleviate tumor hypoxia, promote radiation-induced DNA damage, and ultimately inhibit tumor growth in vivo. The miR181a-2-3p (miR181a) serum levels in patients are predictive of the response to preoperative radiotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) and facilitate personalized treatment. Moreover, miR181a can act as a radiosensitizer by directly targeting RAD17 and regulating the Chk2 pathway. Subsequently, the GDY-CeO nanocomposites with miR181a are conjugated with the iRGD-grafted polyoxyethylene glycol (short for nano-miR181a), which can increase the stability, efficiently deliver miR181a to tumor, and exhibit low toxicity. Notably, nano-miR181a can overcome radioresistance and enhance therapeutic efficacy both in a subcutaneous tumor model and human-patient-derived xenograft models. Overall, this GDY-CeO nanozyme and miR181a-based multisensitized radiotherapy strategy provides a promising therapeutic approach for ESCC.