Recent Advances and Future Directions in 5-Fluorouracil Drug Delivery: A Comprehensive Review.

Given the multiple challenges associated with the clinical use of 5-fluorouracil (5-FU), including pronounced fluctuations in plasma concentrations, significant interindividual metabolic variability, and frequent systemic adverse reactions, this study systematically examines the advantages and prospects of innovative 5-FU delivery strategies. These strategies aim to overcome its clinical limitations. To this end, molecular engineering approaches, such as Prodrug Technology, cocrystal technology, and conjugate design, are utilised to enhance permeability, solubility, and targeted release. In addition, microenvironmental regulation strategies modulate both systemic and tumor microenvironments, enhancing therapeutic efficacy and potentially reversing drug resistance. Furthermore, multifunctional, stimuli-responsive delivery carriers and devices now enable precise, intelligent drug release. Notably, as drug delivery technologies advance, emerging evidence suggests that single strategies cannot fully address the challenges of 5-FU administration. Therefore, multidimensional synergistic approaches significantly improve 5-FU bioavailability, reduce systemic toxicity, and optimize therapeutic outcomes. Looking forward, integrating multiple strategies within a multidisciplinary framework may offer a valuable paradigm for designing delivery systems for pyrimidine-based antimetabolite drugs.