Abstract
Challenges and opportunities in multimodal synergistic therapy for skin fibrosis encompass elucidating the mechanisms of synergistic treatment, optimizing and developing highly coupled combinations, and eliminating therapeutic resistance. This study reveals that the excessively deposited extracellular matrix of hypertrophic scar not only forms a physical barrier for local drug delivery but also generates high mechanical stress, which drives glucocorticoid insensitivity by activating the FAK-AKT-HDAC2 axis in fibroblasts. Both mechanical and biological barriers result in poor outcomes of triamcinolone acetonide therapy for hypertrophic scars. To address this, a chemomechanical antifibrotic approach is engineered by integrating a microneedle-based transdermal delivery platform, immobilized enzymes, and long-acting sustained-release microspheres. This strategy significantly sensitizes scar fibroblasts by disrupting the fibrotic extracellular matrix and the resultant mechanics-induced cellular programs for drug resistance, thus notably reversing the fibrotic characteristics. These findings uncover a mechanism of glucocorticoid resistance and present a multimodal, self-administrable therapy against fibrosis.