A FAPI-based small-molecule drug conjugate alleviates rheumatoid arthritis by targeting pathogenic FAPα-expressing fibroblasts.

The management of rheumatoid arthritis (RA) has advanced into the realm of targeted therapies; however, these therapies often lack tissue specificity and cause systemic adverse effects. Fibroblast-activating protein α (FAPα+) expressing fibroblast-like synoviocytes (FLSs) are critical pathogenic cell components in RA and are particularly abundant in inflamed joints, whereas they are minimal in other tissues. Consequently, FAPα+ FLSs are emerging as promising therapeutic targets for treating RA. However, strategies to specifically target FAPα+ FLSs in RA remain underdeveloped. To bridge this gap, we developed a novel compound, FAPI-Gly-Pro-MTX (FM), which integrates a FAPα+ tracer, FAPα inhibitor (FAPI), with the traditional drug methotrexate (MTX) via a glycine-proline dipeptide that can be cleaved by the dipeptidyl peptidase activity of FAPα. In an arthritis mouse model, FM selectively targeted FAPα+ FLSs in inflamed joints, facilitating the localized release of MTX and resulting in the significant alleviation of arthritis symptoms while minimizing systemic toxicity. Importantly, the presence of FAPI ensured that FM induced cell death specifically when FAPα+ FLSs were presented, thereby enhancing safety. Consequently, FM demonstrated considerable clinical potential as a safe and effective off-the-shelf therapeutic option for targeting FAPα+ FLSs in patients with RA. a FAPα+ FLSs are induced by various inflammatory cytokines in inflamed joints and aggravate inflammation and bone destruction; b FM selectively delivers MTX to FAPα+ FLSs in RA-inflamed joints and minimizes off-target effects; c Conventional MTX administration lacks cell specificity, leading to systemic adverse effects.