Intra-articular metformin-curcumin cationic PLGA nanoparticles rejuvenate articular structure in MIA induced osteoarthritis model via modulating the crosstalk between miR93, TNFAIP3/TLR/NF-κB and AMPK/SIRT1 trajectories

Osteoarthritis (OA), a degenerative bone disease, restrains patient's productivity and quality of life. Herein, the potential of uncoated and hyaluronic acid (HA)-coated cationic - PLGA (cPL) nanoparticles loaded with metformin (MT) and curcumin (Cu) was investigated for IA administration for the first time. Optimized MT-Cu-cPL₂ showed particle size 266.2 ± 2.35 nm, zeta potential +13.6 ± 0.6 mV; entrapment efficiency of 42.56 % ± 0.04 and 93.65 % ± 0.017 for MT and Cu, respectively. Optimized HA-MT-Cu-cPL₄ displayed particle size 254.1 ± 3.96 nm, zeta potential -21.6 ± 0.4 mV; and entrapment efficiency of 71.4 % ± 1.06 and 93.2 % ± 0.93 for MT and Cu, respectively. HA-MT-Cu-cPL₄ demonstrated a sustained release of MT and Cu over 24 h and stability over 3-months at 4 °C. The IA administration of MT-Cu-cPL₂ and HA-MT-Cu-cPL₄ to MIA-induced OA rats revealed their significant antiarthritic potential. Treatment with HA-MT-Cu-cPL₄ showed the most significant repression of OA advancement due to enhancement of miR-93 and TNFAIP3 knee tissue expression levels that have been correlated to upregulation of AMPK/SIRT1 activity and downstream inhibition of TLR4/NF-κB signaling pathway. The optimized nano-formulations also exhibited anti-edematous, anti-nociceptive, and locomotor-enhancing activity, highlighting the IA MT-Cu combinational therapy as a prosperous approach for management of OA.