Chitosan-based nanocomposites for targeted colorectal cancer therapy: design strategies, functionalization, and therapeutic advances.

Colorectal cancer is a major global health concern, accounting for nearly 10% of all cancer deaths and causing over 900,000 deaths annually. Despite therapeutic advances, issues like poor drug bioavailability, systemic toxicity, and drug resistance persist. Chitosan, a naturally derived polysaccharide, has gained attention as a versatile nanocarrier for colorectal cancer therapy due to its pH responsiveness, mucoadhesiveness, and enzymatic biodegradability, which enable site-specific and controlled drug release. This review highlights recent progress in the design and functionalization of chitosan-based nanocomposites for targeted colon delivery. Approaches such as ligand-mediated targeting (e.g., folate, hyaluronic acid), enzyme-triggered systems, and smart hydrogels enhance tumor selectivity and therapeutic efficacy. Moreover, co-delivery systems integrating chemotherapeutics with gene modulators or immunotherapeutics offer solutions to tumor heterogeneity and drug resistance. Preclinical findings indicate improved bioavailability, tumor accumulation, and reduced systemic toxicity, while early clinical studies report favorable safety and pharmacokinetic profiles. Challenges including pH solubility and rapid clearance are being addressed through PEGylation, chemical grafting, and hybrid nanocomposites. Overall, chitosan's multifunctional nature positions it as a promising platform for next-generation, colon-targeted nanomedicine in colorectal cancer treatment.