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Background & Aims To clarify the biological roles, circularization process and secretion pathway of circRHOBTB3 in colorectal cancer (CRC) progression. Methods We performed a comprehensive analysis of circRNA levels in serum exosomes from multiple types of cancer patients in public databases and verified the higher level of circRHOBTB3 in CRC sera versus healthy donors by RT-qPCR. Then, the function of circRHOBTB3 in CRC was investigated in vitro and in vivo. RNA-seq and RNA pull-down assays together with mass spectrometry identified the downstream signals and the binding proteins of circRHOBTB3. Finally, Antisense oligonucleotides (ASOs) were designed to target circularization and secretion elements of circRHOBTB3 for CRC therapy. Results circRHOBTB3 levels were increased in the sera but was downregulated in tissue samples in CRC, and the downregulation was associated with poor prognosis. Furthermore, circRHOBTB3 acts a tumor-suppressive circRNA by repressing metabolic pathways, intracellular ROS production in CRC. Several key elements were discovered to regulate circRHOBTB3 circularization and exosomal secretion. Moreover, SNF8 was identified that sorts circRHOBTB3 into exosomes. Interestingly, we found that CRC cells could actively secrete more circRHOBTB3 than normal cells. According to the sequence of regulatory elements for circularization and exosomal secretion, we designed and synthesized ASOs, which increased circRHOBTB3 expression and blocked circRHOBTB3 exosomal secretion. More importantly, ASOs could inhibit CRC growth and metastasis in vitro and in vivo. Conclusions circRHOBTB3 plays a tumor-suppressive role in CRC and has to be excreted out of cells to sustain cancer cell fitness. ASOs targeting regulatory elements for circularization and exosomal secretion will become a novel antitumor strategy.

The development of colitis-associated colorectal cancer is known to be associated with the inflammation-dysplasia-carcinoma pathway, and thus, chronic inflammation represents an inducer and promoter of cancer. To inhibit the evolution from colitis to colorectal cancer and provide an efficient anticancer therapy, a surface-engineered vanadium carbide MXene nanoenzyme (MXenzyme) is developed with both amino functionalization and gallium doping (Ga/V 2 C-NH 2 ). Benefiting from multiple enzymemimicking activities, MXenzymes have shown great potential to decrease excessive reactive oxygen species and inhibit the levels of proinflammatory cytokines, resulting in good anti-inflammatory effects on dextran sulfate sodium-induced acute colitis. Moreover, the gallium-doped MXene with an amino-functionalized surface can mediate improved MXene-tumor interactions and inhibitory effects on cell proliferation, achieving precise and efficient chemo-photothermal therapy. Elemental doping into MXene is also highlighted as a feasible strategy to achieve the loading and controlled release of gallium. As a result, complete tumor ablation without further recurrence is observed for the colon cancer-bearing mice that receive Ga/V 2 C-NH 2 and near infrared irradiation, while the MXenzyme system displays excellent biocompatibility at both the cellular and animal levels. These findings not only enrich the research of MXene, but also illustrate its efficient therapeutic promise in anti-inflammation and photoenhanced antitumor therapy of colon diseases.

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