Stem Cell-Laden Magnetic Hydrogels for Liver Fibrosis Reversal via Synergistic Magneto-Mechanical Stimulation

As a critical stage in chronic liver disease, liver fibrosis can progress to irreversible damage without timely intervention. Stem cell therapy offers significant therapeutic potential owing to its potent regenerative and immunomodulatory properties. However, its clinical application is challenged by low cell survival, poor targeting, and inadequate paracrine regulation. Here, we present a magnetic hydrogel patch laden with human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) to enhance their antifibrotic efficacy via synergistic magneto-mechanical stimulation. The patch is fabricated through thiol-ene “click” chemistry using multi-thiol-functionalized magnetic nanoparticles as crosslinkers. Molecular dynamics simulations reveal the regulatory mechanism of nanoparticle concentration on the crosslinking topology of the hydrogel network, thereby identifying the optimal formulation with favorable mechanical properties and magnetic responsiveness. Under magneto-mechanical stimulation, the resulting patch significantly enhances the secretion of key antifibrotic factors from hUC-MSCs by activating the PI3K/Akt/mTOR signaling pathway. Moreover, in vitro and in vivo results demonstrate that, under magnetic stimulation, the hUC-MSC-laden magnetic patch significantly inhibits hepatic stellate cell activation, promotes anti-inflammatory macrophage polarization, reduces collagen deposition, and ameliorates the inflammatory microenvironment, thereby effectively reversing liver fibrosis. This study offers a versatile stem cell-based platform for spatiotemporally controlled therapy of liver fibrosis and potentially other fibrotic diseases.