Boosting cutaneous penetration of 3-acetyl-11-keto-β-boswellic acid by glycosaminoglycan-based polysaccharide coated proglycosomes for rheumatoid arthritis therapy.

3-Acetyl-11-keto-β-boswellic acid (AKBA), a plant-derived anti-inflammatory agent, has shown therapeutic potential in the management of rheumatoid arthritis (RA). However, its clinical utility is limited by poor solubility and low bioavailability. To address these challenges, the present study aimed to develop and evaluate surface-engineered proglycosomes (PGS) coated with glycosaminoglycan-based biological macromolecules, hyaluronic acid (HA), and chondroitin sulfate (CS) as (HA-AKBA-PGS and CS-AKBA-PGS) for targeted dermal delivery of AKBA. The optimised HA-AKBA-PGS and CS-AKBA-PGS exhibited vesicle sizes of 122.63 ± 1.84 nm and 108.06 ± 1.30 nm, with the desired surface charge. Fluorescence-based uptake studies in LPS-stimulated RAW 264.7 macrophages confirmed enhanced internalisation of the coated proglycosomes. ELISA analysis revealed significant downregulation of inflammatory markers, including TNF-α, IFN-γ, and IL-6, in treated cells. Ex vivo study of N-AKBA-PGS, HA-AKBA-PGS, and CS-AKBA-PGS embedded Gel demonstrated 3.27-fold, 5.78-fold, and 1.24-fold enhanced skin retention compared to free-AKBA Gel, respectively. The in vivo pharmacodynamic assessment in a CFA-induced arthritic rat model demonstrated a marked reduction in paw thickness and clinical arthritis scores for HA and CS-coated PGS gels compared to free-AKBA Gel. The HA-AKBA-PGS and CS-AKBA-PGS groups showed greater reduction in clinical scores, respectively, supporting the efficacy of these formulations in RA management. These findings suggest that HA- and CS-coated PGS gels offer a promising platform for localized, sustained, and receptor-targeted delivery of AKBA, enabling improved therapeutic outcomes while minimizing systemic exposure in RA therapy.