Natural polysaccharides targeting mitochondrial function for colorectal cancer prevention and treatment: mechanisms and nano-delivery strategies

Background Colorectal cancer (CRC) is a malignant tumor of the digestive system with high incidence and mortality worldwide. Mitochondrial dysfunction plays a central role in the development, progression, and chemotherapy resistance of CRC. Natural polysaccharides have attracted increasing attention in anti-CRC research in recent years due to their wide sources, low toxicity, good biocompatibility, and multi-target activities. Objective To systematically review the molecular mechanisms by which natural polysaccharides target mitochondrial dysfunction to prevent and treat CRC, and to summarize the research progress of nano-delivery strategies. Methods A systematic search was conducted in PubMed, Web of Science, Scopus, and SinoMed databases for literature published from January 1, 2015 to June 3, 2026. A total of 89 articles were included for analysis. Results Natural polysaccharides exert anti-CRC effects through synergistic actions of multiple pathways, including regulation of reactive oxygen species homeostasis, induction of mitochondrial apoptosis and autophagy, remodeling of the tumor immune microenvironment, and protection of intestinal barrier function. Their bioactivities are closely related to molecular weight, monosaccharide composition, glycosidic bond type, branching structure, and chemical modification. Nano-delivery technologies can significantly improve their targeting efficiency and therapeutic activity. Regarding clinical studies, current evidence mainly focuses on the combined use of natural polysaccharides with chemotherapy and the management of cancer-related symptoms; direct clinical evidence targeting CRC resistance remains limited. Conclusion Mitochondria-targeting nano-systems based on natural polysaccharides provide a promising multi-target strategy for CRC prevention, treatment, and reversal of chemotherapy resistance. However, current evidence has limitations, including inconsistent structural characterization, lack of direct co-localization evidence, and insufficient pharmacokinetic-pharmacodynamic evaluations.