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Covalently bonded Eudragit S-100 (EU) and chitosan (CS) based colon-specific nanoparticles (CSE NPs) were fabricated as drug carriers for treating colorectal cancers through oral administration. Thiolation of EU and CS prevents the usage of the cross-linking agent. This gives an advantage over the shortcomings of existing EU- and CS-based delivery systems that are associated with large sized nanoparticles with a broad range of size distribution. Paclitaxel (PTX)-loaded CSE NPs presented an efficacy of 8–10% after 48 h of treatment on the HCT 116 cell line signifying uniform distribution of drug inside the cells. About 66% accumulation of cell population was observed in G2/M phase for PTX-loaded CSE NPs, indicating arrest of cell division during the mitotic phase. Biodistribution studies on male Balb/C mice demonstrated retention of CSE NPs in the colon region up to 24 h post oral administration. These …