<p>Developing well-tolerated pharmaceutical formulations remains a major challenge in drug delivery. Polysaccharide-based biopolymers, such as chitosan and pectin, provide a renewable and biocompatible platform for modified drug release. Despite its efficacy in Chagas disease, benznidazole (BNZ) is associated with a significant rate of side effects, which often compromise patient adherence. In this study, interpolyelectrolyte complex (IPEC) microparticles loaded with BNZ, using a melt extrusion technique without solvents, were designed and developed to provide therapeutic alternatives for Chagas disease treatment. The incorporation of polyethylene glycol facilitated polymer processing, enabling high-yield microparticle production without organic solvents. The crystalline nature of BNZ was reduced, leading to a more homogeneous distribution within the microparticles, which exhibited excellent flow properties and were suitable for hard gelatin capsule formulation. The system enhanced BNZ solubility in simulated gastric fluid, improved fluid uptake, and demonstrated mucoadhesive properties. Moreover, it provided a delayed BNZ dissolution, independent of dissolution media. Notably, the IPEC-based formulation improved the antiparasitic activity of BNZ against <i>Trypanosoma cruzi</i> while reducing its cytotoxic effects on human endothelial cells. This scalable, biocompatible platform offers a promising strategy for optimizing Chagas disease treatment by potentially minimizing side effects and improving overall therapeutic outcomes.</p> Graphical Abstract <p></p>