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5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for colorectal cancer (CRC) owing to its potent anticancer effects. However, severe systemic side effects and poor drug accumulation in the CRC tissues limit its efficacy. This study aimed to develop 5-FU crystal-incorporated, pH-responsive, and release-modulating poly(d,l-lactide-co-glycolide)/Eudragit FS hybrid microparticles (5FU-EPMPs) for the local CRC-targeted chemotherapy. Approximately 150 μm 5FU-EPMPs were fabricated via the S/O/W emulsion solvent evaporation method, with 7.93 ± 0.24% and 87.23 ± 2.64% 5-FU loading and encapsulation efficiencies, respectively. Drug release profiles in a simulated pH environment of the gastrointestinal tract revealed that premature 5-FU release in the stomach and small intestine was prevented, thereby minimizing systemic 5-FU absorption. After reaching the colon, 5-FU was continuously released for >15 h, allowing long-term exposure of CRC tissues to sufficient 5-FU concentrations. Furthermore, in a CRC mouse model, the 5FU-EPMPs showed potent inhibition of tumor growth without signs of systemic toxicity. Thus, the 5FU-EPMPs represent a promising drug delivery system for local CRC-targeted chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)