Rational design of metal-organic frameworks to deliver methotrexate for targeted rheumatoid arthritis therapy.

Methotrexate (MTX) has been used as an anchor drug for the treatment of rheumatoid arthritis (RA), while the patients with chronic MTX administration suffer from severe side-effects. To this end, targeted delivery of MTX by nanomedicine has attracted great interest. In this work, we aimed to employ metal-organic frameworks (MOFs) as nanocarrier to deliver MTX by virtue of its facile and green preparation and exceptionally high drug loading. While MTX could be easily and effectively loaded via different MOF construction strategies, such as direct coordination, physical encapsulation, and covalent conjugation, we found that most of the MTX loading MOFs showed premature and burst drug release, attributable to the unstable coordination between MTX and metals. To address this issue, we rationally designed the MOFs by conjugating MTX with tannic acid (TA) at 2:1 M ratio and then coordinating with ferric ion (Fe3+), followed by surface modification of hyaluronic acid (HA). The resulting MOFs achieved ultra-high drug loading (45%) and sustained drug release, and could selectively recognize the diseased cells for anti-inflammatory effect. The in vivo therapeutic evaluation suggested that the MOFs could enhance the anti-rheumatic activity of MTX while minimizing its toxic effects by targeted drug delivery, resulting in improved therapeutic index. This work provides a biocompatible nano-platform to deliver MTX for RA treatment, and importantly, calls for special attention to the gap between MOFs design and their biological applications, and the gap needs to be filled by careful evaluation of in vivo stability and burst drug release.