Combination chemotherapy is widely utilized in treating colorectal cancer (CRC), particularly for patients who are ineligible for surgery or those with metastatic CRC (mCRC). While this therapeutic method has demonstrated efficacy in managing CRC and mCRC, its broader clinical application is limited due to the unique physical properties, mechanisms of action, and pharmacokinetics of different chemotherapeutic drugs. Consequently, achieving satisfactory treatment outcomes proves to be challenging. Nanotechnology has given rise to innovative drug systems that are precise, controllable, and highly efficient in drug delivery. These nanoscale drug delivery systems can integrate the advantageous aspects of various therapeutic modalities, including chemotherapy, gene therapy, and immunotherapy. This review aims to explain the application of nano-drug delivery system in the treatment of colorectal cancer. Through its unique physical/chemical properties and biological functions, it can solve the limitations of traditional therapy and achieve more accurate, efficient and safe treatment. The advantages/disadvantages, physical and chemical characteristics of various drug delivery systems are described in detail, and suggestions on selecting reasonable NDDSs according to different drug combination methods are given to achieve the best therapeutic effect. This review paper presents an exhaustive summary of the diverse range of drugs utilized in chemotherapy, in addition to outlining strategies for effectively integrating chemotherapy with other treatment modalities. Furthermore, it delves into the principle of selecting carriers for various drug combinations.Copyright © 2025 Elsevier B.V. All rights reserved.