Oral Nanomotor-Enabled Mucus Traverse and Tumor Penetration for Targeted Chemo-Sono-Immunotherapy against Colon Cancer

Abstract 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.