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 (MnOx)‐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.

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