Targeted drug delivery systems have become a crucial tool in the treatment of cancer, offering the potential to deliver medications directly to the tumor site. One such drug commonly used in chemotherapy is 5-Fluorouracil (5-FU), which has shown effectiveness in treating various solid tumors, particularly colon cancer. This type of cancer poses a significant public health concern, with a high incidence and mortality rate globally. To improve the delivery of 5-FU, this study focused on designing and developing polymeric blends within alginate nanoparticles through the incorporation of different pH-sensitive polymers. Microfluidic systems were employed to synthesize and optimize these polymeric blends, aiming to enhance the encapsulation efficiency of 5-FU in alginate-based nanoparticles. Various polymers, including Eudragit (E, L, RL, RS) and Poly Lactic-co-Glycolic Acid (PLGA), were incorporated into the alginate matrix. Each polymer showed promising results in improving the characteristics of 5-FU loaded alginate nanoparticles. The particles were characterized for the mean hydrodynamic diameter (MHDs) , polydispersity index (PDI), and zeta potential values using dynamic light scattering by zetasizer. Among the polymers tested, PLGA exhibited the highest increase in encapsulation efficiency for 5-FU, with encapsulation efficiencies of 39.9%, 28.2%, and 73.6% achieved at loading percentages of 25%, 50%, and 75%, respectively. Eudragit E also improved the encapsulation efficiency of 5-FU in alginate NPs by 44.6%, 12.9%, and 19.3%, respectively, while Eudragit L improved the efficiency by 34.1%, 43.2%, and 42.4%, respectively. Additionally, Eudragit RS and Eudragit RL both enhanced the encapsulation efficiency of 5-FU in alginate nanoparticles, with Eudragit RS showing slightly higher percentages at 31.42%, 21.60%, and 67.03%, and Eudragit RL at 46.58%, 27%, and 64.56%, respectively. The developed drug delivery system exhibited an improvement in the therapeutic effectiveness of 5-Fu in alginate-based nanoparticles by incorporating pH-sensitive polymeric blends. The enhancement was necessary because when alginate is used as a standalone polymer for encapsulating 5-FU, the encapsulation efficiencies were significantly lower, with values of only 5.2%, 4.9%, and 6.1% respectively. These promising findings suggest the potential of this delivery system for targeted delivery of 5- FU to the colon, offering a more effective treatment approach for colon cancer patients, ultimately leading to advancements in drug delivery technologies.