A Self-Assembled Irinotecan Nanomedicine Abrogates Steatohepatitis-Induced Liver Metastasis and Potentiates Antitumor Efficacy against Colorectal Cancer

  • ACS Nano. 2026 May 5;20(17):13086-13104. doi: 10.1021/acsnano.6c00855.
Mengxi Xiang  1  2  3  4 ,  Cheng Zhou  1  2  3  5  4  6 ,  Chundong Yao  1  7  2  3  4 ,  Jia Liu  1  2  3  4 ,  Lin Wang  1  7  2  3  4 ,  Zheng Wang  1  2  3  5  4  6
Affiliations
  • 1. Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2. Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan 430022, China.
  • 3. Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Wuhan 430022, China.
  • 4. Key Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei 430022, China.
  • 5. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 6. Clinical Research Center of Minimally Invasive Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 7. Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
PMID: 42007878 DOI: 10.1021/acsnano.6c00855
Abstract

Irinotecan is a widely used chemotherapeutic agent for the treatment of advanced and metastatic colorectal Cancer (CRC). However, its clinical application remains unsatisfactory due to its side effects and limited efficacy. Here, we first demonstrate that irinotecan promotes liver metastasis in CRC by inducing chemotherapy-related steatohepatitis, which is an understudied side effect of irinotecan. To abrogate the prometastatic effect of irinotecan, we employ indole-3-carbinol (I3C), an Aryl Hydrocarbon Receptor (AHR) agonist, to develop a self-assembled nanomedicine (termed NICER). NICER abolishes liver metastasis driven by irinotecan-induced steatohepatitis through activating the AHR/CPT1A axis and promoting fatty acid oxidation of hepatocytes. Importantly, NICER also significantly potentiated the antitumor effect of irinotecan. It markedly enhances cellular uptake of irinotecan via caveolin-dependent endocytosis, enabling direct delivery to the endoplasmic reticulum (ER) to induce lethal ER stress. Meanwhile, I3C encapsulated in NICER inhibits glycolysis by activation of AHR. In subcutaneous and liver metastatic CRC models, NICER demonstrates potent antitumor efficacy, reducing the tumor burden by 74.6% and 96.2%, respectively, while also exhibiting good biosafety. In summary, this work synergistically abrogates the prometastatic adverse effect of irinotecan and enhances its antitumor efficacy, presenting a promising strategy to potentiate irinotecan-based chemotherapies.

Keywords
colorectal cancer; irinotecan; liver metastasis; nanomedicine; steatohepatitis.
Products