Hyaluronic acid-coated ZIF-8 nanoparticles for enhanced and controlled methotrexate delivery in rheumatoid arthritis

Methotrexate (MTX) remains a cornerstone in rheumatoid arthritis (RA) therapy; however, its clinical utility is often limited by systemic side effects and suboptimal bioavailability, necessitating higher doses. In this study, we report the synthesis of hyaluronic acid (HA)-coated ZIF-8 nanoparticles (NPs) encapsulating MTX as a targeted drug delivery platform to enhance its accumulation in inflamed tissues. Utilizing an in situ encapsulation method, MTX was incorporated into ZIF-8 NPs, followed by HA coating to enable CD44 receptor-mediated targeting of inflammatory macrophages. The in situ loading achieved an entrapment efficiency (EE%) of 68.96 % and a loading capacity (LC%) of 30.88 %. Drug release was evaluated under physiological (pH = 7.4) and acidic (pH = 5.6) conditions simulating inflamed microenvironments. After 47 h, the cumulative release reached 73.64 % for MTX@ZIF-8s and 59.16 % for HA/MTX@ZIF-8s at neutral pH. However, complete release (100 %) was observed under acidic conditions for both formulations, indicating a pH-responsive and sustained release profile. Cytotoxicity and cellular uptake assays using RAW 264.7 macrophages confirmed enhanced biocompatibility and targeted internalization of HA-coated MTX-loaded NPs. These findings demonstrate that HA-coated ZIF-8 NPs represent a promising strategy for targeted and controlled MTX delivery in RA treatment, potentially improving therapeutic efficacy while minimizing systemic toxicity.