Coffee-derived self-anti-inflammatory polymer as drug nanocarrier for enhanced rheumatoid arthritis treatment

Systemic administration of the anti-rheumatic drug methotrexate (MTX) for a long period of time may lead to therapeutic tolerance, various adverse effects, and potential harm to the immune system. Therapeutic nano-delivery carriers constructed based on biologically active phenols provide a promising approach to enhance the therapeutic effect of anti-rheumatic drugs. Caffeic acid, a natural compound with anti-inflammatory properties, holds significant potential in the treatment of diverse inflammatory conditions. In this paper, we first constructed a nano-delivery platform for MTX using caffeic acid-based polyphenol polymer Ph-CaA-OH (PCOH), and investigated the treatment of rheumatoid arthritis (RA) at low drug administration doses (2.5 mg/kg). PCOH nanoparticles (NPs) could inhibit lipopolysaccharides-stimulated macrophage inducible nitric oxide synthase (iNOS) expression and pro-inflammatory differentiation in vitro. In vivo imaging revealed the rapid accumulation and sustained presence of PCOH NPs at inflamed joints in collagen induced-arthritis (CIA) mice. Therapeutic evaluation of CIA mice demonstrated that MTX@PCOH NPs were superior to free MTX in reducing the progression of RA and decreasing the expression of multiple pro-inflammatory cytokines without significant toxic effects. By enhancing drug aggregation at inflammatory joints and capitalizing on the synergistic effects of active carriers, MTX@PCOH NPs effectively minimized the required drug dosage and mitigated toxic side effects in RA treatment. The application of PCOH NPs to RA treatment provides a new strategy for the development of safer and more effective anti-RA nanomedicines.