ABSTRACT Colorectal cancer (CRC) presents significant therapeutic challenges because of chemoresistance, systemic toxicity, and the complexity of the tumor microenvironment (TME). Nanodrug delivery systems (NDDS) have emerged as versatile platforms capable of overcoming these limitations by enhancing tumor accumulation, improving pharmacokinetics, and enabling controlled or stimuli‐responsive drug release. This review summarizes recent advances in NDDS for CRC therapy, focusing on targeted delivery strategies—including passive targeting via the enhanced permeability and retention (EPR) effect and active targeting using ligands for receptors such as CD44, EGFR, and folate receptor. Oral NDDS designed to overcome gastrointestinal barriers through pH‐, enzyme‐, and mucus‐responsive mechanisms are also discussed, as well as TME‐responsive systems aimed at reversing multidrug resistance (MDR) by exploiting tumor acidity, hypoxia, and redox imbalance. Applications in immunotherapy and multimodal combination therapies are highlighted, emphasizing strategies that convert immunologically “cold” tumors into “hot” tumors. Finally, clinical translation challenges, including interpatient variability, biosafety, and scalable manufacturing, are evaluated. Overall, NDDS provide a multifunctional and adaptable platform for precision CRC therapy.
Wei et al. (2026) studied this question.