Synovial Targeting and Redox-Triggered Release: A Dual Strategy in Peptide-Drug Conjugates for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. To overcome the rapid clearance and systemic side effects of sinomenine (SIN), three critical components of peptide-drug conjugates (PDCs), including the targeting peptide, linker, and payload, were optimized, and two synovial homing peptide-sinomenine conjugates, SIN-SS-DRL and dSIN-SS-DRL, linked via reduction-sensitive disulfide bonds, were developed. Both new conjugates exhibited markedly improved plasma stability and demonstrated selective, glutathione-triggered release of SIN, with LC-MS confirming an accelerated and more complete release from the dual-disulfide conjugate. In vitro, they effectively suppressed pro-inflammatory cytokines, while in vivo studies in adjuvant-induced arthritis mice showed significant alleviation of joint inflammation and bone damage, with efficacy comparable to or exceeding methotrexate. These results highlight the potential of dual disulfide-linked PDCs as a promising targeted therapy for RA, integrating active synovial homing and passive redox-responsive release to achieve superior therapeutic outcomes with favorable safety profiles.