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

Small. 2022 Oct;18(42):e2203466. doi: 10.1002/smll.202203466. Epub 2022 Sep 18.


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 (H2 O2 )/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 H2 O2 and US irradiation, inducing efficient mucus-traversing and deep tumor penetration. The excess H2 O2 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.

Keywords: mucus traversing; nanomotors; oral administration; synergistic treatment; tumor penetration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alginates
  • Animals
  • Antigens, Neoplasm
  • Cell Line, Tumor
  • Chitosan* / pharmacology
  • Chondroitin Sulfates / pharmacology
  • Chondroitin Sulfates / therapeutic use
  • Colonic Neoplasms* / drug therapy
  • Fibroins*
  • Hydrogels / pharmacology
  • Hydrogen Peroxide / pharmacology
  • Immune Checkpoint Inhibitors
  • Mucus
  • Nanoparticles* / therapeutic use
  • Neoplasms* / therapy
  • Oxygen / pharmacology
  • Singlet Oxygen / pharmacology
  • Tumor Microenvironment


  • Singlet Oxygen
  • Chitosan
  • Hydrogen Peroxide
  • Chondroitin Sulfates
  • Immune Checkpoint Inhibitors
  • Fibroins
  • Oxygen
  • Antigens, Neoplasm
  • Hydrogels
  • Alginates