Fibroblast-targeted MLN4924 suppresses autoimmune myocarditis by dually modulating IL-17A and TGF-β pathways

Area of Science:

• Cardiovascular Research
• Immunology
• Nanomedicine

Background:

• Myocarditis is a primary cause of heart failure in young people, often progressing to dilated cardiomyopathy via inflammation-induced cardiac fibrosis.
• Cardiac fibroblasts (CFs) play a crucial role in myocarditis by mediating inflammatory responses (IL-17A) and fibrotic remodeling (TGF-β).
• Current therapies lack the ability to simultaneously address both the inflammatory and fibrotic pathways in CFs.

Purpose of the Study:

• To investigate the therapeutic potential of the neddylation inhibitor MLN4924 in experimental autoimmune myocarditis (EAM).
• To engineer and evaluate a fibroblast-targeted nanoparticle (FMlipo@MLN4924) for enhanced delivery and efficacy of MLN4924.
• To elucidate the mechanisms by which MLN4924 modulates IL-17A and TGF-β signaling in cardiac fibroblasts.

Main Methods:

• MLN4924 was tested in a mouse model of EAM.
• A fibroblast-targeting biomimetic nanoparticle (FMlipo@MLN4924) was developed and characterized.
• In vitro and in vivo studies assessed the delivery efficiency and therapeutic effects of FMlipo@MLN4924, including immune cell infiltration, fibrosis, and cardiac function.

Main Results:

• Systemic MLN4924 treatment reduced myocardial inflammation, cardiac fibrosis by ~50%, and preserved cardiac function in EAM mice.
• MLN4924 demonstrated dual suppression of IL-17A-induced chemokine production and TGF-β-induced fibrotic activation in CFs.
• FMlipo@MLN4924 showed >2.5-fold increased cardiac accumulation versus non-targeted liposomes, leading to superior efficacy in suppressing inflammation and fibrosis without toxicity.

Conclusions:

• MLN4924 exhibits dual anti-inflammatory and anti-fibrotic effects in autoimmune myocarditis by targeting IL-17A and TGF-β pathways in CFs.
• Fibroblast-membrane camouflaging of MLN4924 via FMlipo@MLN4924 enhances drug delivery and therapeutic outcomes.
• This targeted approach represents a promising precision medicine strategy for immune-mediated cardiac injury with significant translational potential.