Development, characterization, and optimization of folate-chitosan surface-modified PLGA-decorated mesoporous silica nanoparticles for effective delivery of leflunomide for the management of rheumatoid arthritis.

Folate-chitosan surface modification of PLGA-decorated mesoporous silica nanoparticles (FC-PLGA-MSNs) was implemented to improve the delivery of leflunomide (LEF) for the management of rheumatoid arthritis (RA). These nanoparticles were designed to address LEF's poor bioavailability and side effects, such as hepatotoxicity and gastrointestinal distress, by enhancing oral delivery and targetability to inflamed joints. Various MSNs were prepared and optimized with different levels of pH and silica precursor (TEOS). The optimized MSNs exhibited a size of 94.2 ± 3.3 nm, a zeta potential of -50.2 ± 4.5 mV, and a yield of 2.401 ± 0.17gm. Optimized MSNs were loaded with LEF with entrapment efficiency of 79.25 ± 3.84 %, subsequently coated with PLGA, and surface modified with folate-chitosan, producing FC-LEF-PLGA-MSNs demonstrating a nanometric size range and sustained drug release. The therapeutic efficacy of the FC-LEF-PLGA-MSNs was evaluated in a rat model of RA, showing significant antirheumatic effects compared to free and marketed LEF. Oral administration of the nanoparticles after RA induction significantly reduced joint swelling and histopathological damage. Additionally, the FC-LEF-PLGA-MSNs suppressed inflammatory cytokine levels, including TNF-α and IL-6, by 52.86 % and 55.12 %, respectively. These results demonstrate that FC-LEF-PLGA-MSNs provide an effective and safer alternative to free LEF for RA treatment.