The therapeutic outcomes of oral nanomedicines against colon cancer are heavily compromised by their lack of specific penetration into the internal tumor, favorable anti-tumor activity, and activation of anti-tumor immunity. Herein, hydrogen peroxide (H₂O₂)/ultrasound (US)-driven mesoporous manganese oxide (MnO_x)-based nanomotors are constructed by loading mitochondrial sonosensitizers into their mesoporous channels and orderly dual-functionalizing their surface with silk fibroin and chondroitin sulfate. The locomotory activities and tumor-targeting capacities of the resultant nanomotors (CS-ID@NMs) are greatly improved in the presence of H₂O₂ and US irradiation, inducing efficient mucus-traversing and deep tumor penetration. The excess H₂O₂ in the tumor microenvironment (TME) is decomposed into hydroxyl radicals and oxygen by an Mn²⁺-mediated Fenton-like reaction, and the produced oxygen participates in sonodynamic therapy (SDT), yielding abundant singlet oxygen. The combined Mn²⁺-mediated chemodynamic therapy and SDT cause effective ferropotosis of tumor cells and accelerate the release of tumor antigens. Importantly, animal experiments reveal that the treatment of combining oral hydrogel (chitosan/alginate)-embedding CS-ID@NMs and immune checkpoint inhibitors can simultaneously suppress the growth of primary and distal tumors through direct killing, reversion of immunosuppressive TME, and potentiation of systemic anti-tumor immunity, demonstrating that the CS-ID@NM-based platform is a robust oral system for synergistic treatment of colon cancer.

中文翻译：

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口腔纳米马达支持的粘液遍历和肿瘤渗透用于结肠癌的靶向化疗-声学-免疫疗法

由于缺乏对内部肿瘤的特异性渗透、良好的抗肿瘤活性和抗肿瘤免疫的激活，口服纳米药物对结肠癌的治疗效果受到严重影响。在此，过氧化氢 (H ₂ O ₂ )/超声 (US) 驱动的介孔氧化锰 (MnO _x ) 基纳米马达是通过将线粒体声敏剂加载到它们的介孔通道中并用丝素蛋白和硫酸软骨素有序地双重功能化它们的表面来构建的. _{在存在 H 2} O ₂的情况下，所得纳米马达 (CS-ID@NMs) 的运动活动和肿瘤靶向能力得到极大改善和超声照射，诱导有效的粘液穿越和深度肿瘤穿透。肿瘤微环境（TME）中过量的H ₂ O _2通过Mn ²⁺介导的类芬顿反应分解为羟基自由基和氧，产生的氧参与声动力治疗（SDT），产生丰富的单线态氧。结合的 Mn ²⁺介导的化学动力学疗法和 SDT 可引起肿瘤细胞的有效铁蛋白沉积并加速肿瘤抗原的释放。重要的是，动物实验表明，结合口服水凝胶（壳聚糖/藻酸盐）嵌入 CS-ID@NMs 和免疫检查点抑制剂的治疗可以通过直接杀伤、逆转免疫抑制性 TME 和增强系统抗肿瘤免疫，表明基于 CS-ID@NM 的平台是一种强大的口服系统，可协同治疗结肠癌。