Reversing fibroblast-to-myofibroblast transition using surface-engineered nanoparticles to potentially ameliorate fibrotic diseases.

Abstract

Fibroblast-to-myofibroblast transition (FMT) is cellular transformation process driving the pathogenesis of fibrotic disorders such as pulmonary fibrosis and scleroderma. Despite advances in anti-fibrotic therapies, existing treatments primarily slow disease progression rather than directly targeting extracellular matrix (ECM)-secreting myofibroblasts, and cannot reverse established fibrosis. In this work, a nanoparticle-enabled, anti-fibrotic approach is demonstrated to reverse the FMT in myofibroblasts via targeting cadherin-2 (CDH2), a cell-surface maker of myofibroblasts, using melanin nanoparticles with surface-engineered CDH2 antibody (CDH2-MelNPs). Treatment with CDH2-MelNPs promotes myofibroblast-to-fibroblast transition (MFT, reversed FMT), significantly suppressing ECM deposition, proliferation, migration, and invasive behavior of myofibroblasts, while concurrently mitigating tissue contractility and stiffness, the hallmarks of fibrosis. Mechanistic studies reveal that this nanoparticle-driven MFT is regulated by the inhibition of the Rho signaling, a critical regulator of FMT. Overall, these findings propose an alternative therapeutic avenue to potentially halt or reverse a broad spectrum of fibrotic diseases. The manipulation of fibroblast/myofibroblast phenotype using nanoparticles may also serve as a promising tool in tissue engineering, enabling precise control over tissue remodeling.