Advances in leflunomide therapy: mechanistic insights, clinical uses, and drug delivery approaches

Leflunomide (LEF) is a disease-modifying antirheumatic drug that primarily inhibits dihydroorotate dehydrogenase, thereby suppressing de novo pyrimidine synthesis and limiting activated lymphocyte proliferation. Beyond rheumatoid arthritis, its therapeutic potential has been explored in other inflammatory and autoimmune conditions. However, oral use is constrained by limited solubility, variable bioavailability, and systemic adverse effects. To address these limitations, diverse drug delivery platforms, including lipid-based systems, polymeric carriers, hydrogels, implants, and nanostructured formulations, have been investigated to improve localization, sustain release, and enhance therapeutic efficiency. These approaches aim to reduce toxicity while improving pharmacokinetic behaviour and patient outcomes. This review highlights how formulation design may expand the clinical utility of LEF and support more precise and safer treatment strategies for chronic inflammatory diseases.