Colon-specific drug delivery systems (CTDDS) have gained much more attention for treating local and systemic diseases such as inflammatory bowel disease (IBD), ulcerative colitis, and colorectal cancer with their ability to improve therapeutic efficacy and outcomes. This review highlights the importance of natural polymers (polysaccharides and proteins) for the development of an attractive delivery system for CTDD. Natural polymers are the ideal choice for targeted drug delivery as they show better biocompatibility, biodegradability, and responsiveness to colon stimuli. In this review, the current challenges are colonic environment variability and drug stability, as well as the opportunities for innovative design through intelligent materials. The various advanced colon-targeting approaches include pH-microbiota combination systems, pH-time combination systems, and microbiota-sensitive coating approaches that are systematically discussed. The formulation approaches utilizing hydrogels, biofilms, microparticles, and nanoparticles based on polysaccharides are also examined. Moreover, innovative inventions like MOFs (metal–organic frameworks), 3D printing technologies, and the optimization of polymer blends by AI are described as the upcoming promising avenues to make CTDD more precise and personalized. This review provides the current scenario, prospects, and highlights the requirements of an interdisciplinary approach to overcome current challenges and to fully achieve the potential of natural polymer-based colon-targeted therapies.
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