A biomimetic, triggered-release micelle formulation of methotrexate and celastrol controls collagen-induced arthritis in mice

He Ren; Zewen Wu; Jingxuan Li; Nan Zhang; Coo Yee Nah; Jiexin Li; Jingyu Zhang; Jonathan F. Lovell; Liyun Zhang; Yumiao Zhang

doi:10.1002/bmm2.12104

BMEMat ›› 2024, Vol. 2 ›› Issue (4) : e12104 DOI: 10.1002/bmm2.12104

RESEARCH ARTICLE

A biomimetic, triggered-release micelle formulation of methotrexate and celastrol controls collagen-induced arthritis in mice

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Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone. RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the joints. Herein, we developed a biomimetic formulation via co-loading the anti-inflammatory agent Celastrol (Cel) along with the stabilizer Vitamin K (VK) in antirheumatic methotrexate (MTX)-conjugated Pluronic F127 (F127) micelles. Micelles were then coated with B cell derived membrane, yielding MTX loaded Cel Micelle (CeViM)-micelle@B, which were investigated for RA treatment. VK, used at levels well within safety margins, was identified as a carrier compound that could stabilize Cel within micelles, increasing the encapsulation efficiency of Cel. In addition, MTX, a front-line RA therapeutic, was chemically grafted to F127 via a responsive linker sensitive to the chemically reducing environments. As such, CeViM-micelle@B released pristine MTX in response to the intracellular reducing environments, which combined with Cel to suppress pro-inflammatory responses. B cell membrane coating enhanced accumulation of CeViM-micelle@B in joints, leading to a 75% decrease of inflammatory cytokine secretion in vitro, and significantly ameliorated cartilage and bone structures in the collagen-induced arthritis murine model. Taken together, this biomimetic nanoparticle holds potential as a nextgeneration targeted RA treatment.

Keywords

co-loading / micelle / microenvironment-responsive / rheumatoid arthritis / self-immolative

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He Ren, Zewen Wu, Jingxuan Li, Nan Zhang, Coo Yee Nah, Jiexin Li, Jingyu Zhang, Jonathan F. Lovell, Liyun Zhang, Yumiao Zhang. A biomimetic, triggered-release micelle formulation of methotrexate and celastrol controls collagen-induced arthritis in mice. BMEMat, 2024, 2(4): e12104 DOI:10.1002/bmm2.12104

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