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

Abstract

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 CeO2 nanoparticles to form GDY–CeO2 nanocomposites, which exhibit superior catalase‐mimic activity in decomposing H2O2 to O2 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–CeO2 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–CeO2 nanozyme and miR181a‐based multisensitized radiotherapy strategy provides a promising therapeutic approach for ESCC.

Effects of preoperative radiotherapy on survival of patients with stage II and III esophageal squamous cell carcinoma

“…Overall, PRT has become a hot spot in the field of locally advanced ESCC treatment. [ 21 ] After ESCC patients experienced surgical resection and reconstructed the digestive tract, most of postoperative patients with ESCC have a poor physical status and severe nutritional status. Preoperative neoadjuvant therapy is considerably easier to tolerate than postoperative adjuvant therapy.…”

Versatile carbon nanoplatforms for cancer treatment and diagnosis: strategies, applications and future perspectives

“…Radioresistance is another tricky challenge that limits the antitumor therapeutic efficacy in clinic, which is resulted from tumor hypoxia, improved DNA repair function, and the existence of CSCs 73 . To address the two issues above, Zhou et al developed a GDY-based nanoplatform that firmly anchored and dispersed CeO 2 nanoparticles (NPs) to form GDY-CeO 2 nanocomposites, which displayed excellent catalase activity due to CeO 2 NPs, remarkably relieving tumor hypoxia through the decomposition of H 2 O 2 into O 2 ( Figure 8 A ) 30 . Moreover, miR181a, a miRNA-based formulation, which was capable of targeting RAD17 and regulating the Chk2 pathway to induce DNA damage and apoptosis, was loaded on GDY-CeO 2 nanocomposites to elevate the sensitivity of radiotherapy against esophageal squamous cell carcinoma (ESCC).…”

“…Statistical analysis was performed by a two-tailed, unpaired Student's t -test, ** p < 0.01. Reproduced with permission from 30 , copyright 2021, Wiley-VCH.…”

“…Construction of (A) Nano-miR181a complexes. Adapted with permission from 30 , copyright 2021, Wiley-VCH, (B) GCDM nanoparticle. Adapted with permission from 31 , copyright 2021, Wiley-VCH, (C) TTIS nanoparticle.…”

Activatable “Matryoshka” nanosystem delivery NgBR siRNA and control drug release for stepwise therapy and evaluate drug resistance cancer

“…The large pore size of MONs make siRNA can not only be adsorbed on the surface but also can be co-loaded with small-sized therapeutic agents into the mesopores to achieve long-term stable release. It is generally believed that compared with negatively and neutrally charged nanomaterials, positively charged has a higher cellular uptake rate [ 43 ], but on the contrary, cationic are easily aggregated and have an adverse immune response, our study uses “invisible" PEG to break this bottleneck. PEGylated make the nanocarriers stably in the circulatory and PEG acid-detachment make nanoparticle turn positive in the tumor microenvironment (TME) to promote endocytosis, at the same time, nanosystem can protect the siRNA against degradation and a reduction of the off-target effects [ 44 ].…”