The objective of this study was to develop and optimize mesalamine-loaded polyelectrolyte complex (PEC) nanoparticles for the treatment of inflammatory bowel disease (IBD) using a central composite experimental design. Mesalamine, a pharmaceutical classified as a Biopharmaceutics Classification System (BCS) Class IV drug due to its poor solubility and permeability, short half-life (0.5–2 h), and challenges in patient compliance, was selected as the model drug for this study. PECs were synthesized by titrating sodium carboxymethyl cellulose (Na-CMC) and chitosan, with the experimental compositions determined using Design Expert® 7.0 software. Formulations were optimized by varying concentrations of chitosan and Na-CMC, considering particle size and encapsulation efficiency (EE%) as the response variables. The optimized PEC nanoparticles were subsequently coated with Eudragit S-100 (ES-100) to enable targeted delivery to the colon. The uncoated nanoparticles had a particle size of 234.9 ± 3.8 nm and a zeta potential of 27.90 ± 2.41 mV. After coating, these values were altered to 319.2 ± 4.1 nm and −13.45 ± 4.13 mV, indicating a shift to a slightly negative surface charge, which contributes to the stability and colon-targeting properties of the nanoparticles. Morphological analysis confirmed that the nanoparticles maintained a roughly spherical shape and that the polymer did not chemically interact with the encapsulated drug. The optimized formulation demonstrated an encapsulation efficiency of 62.26 ± 2.03 %. Drug release studies conducted in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4) showed that uncoated nanoparticles released 91.2 ± 4.5 % of the drug over 48 h, while coated nanoparticles released 74.9 ± 2.9 %, as determined by ANOVA analysis. These findings suggest that the coating effectively extends mesalamine release over time, making this formulation a promising candidate for targeted IBD therapy.