Deformability-augmented mesenchymal stem cells post-enucleation for efficient mRNA intervention of pulmonary fibrosis in rodent model

Stem cell therapy has demonstrated significant therapeutic potential. However, the relatively large cellular diameter increases the likelihood of entrapment within capillaries, impeding the migration of stem cells to disease foci. We herein propose an enucleation strategy to enhance cell deformability, significantly improving vascular transit efficiency. Computational modelling, combined with experimental investigations using a microfluidic platform, revealed that increased cellular deformability, rather than a reduction in diameter, plays a greater role in facilitating cell transit, thereby challenging traditional perspectives on the cell mechanics. Observations of pulmonary vasculature using optical tissue clearing and fluorescence micro-optical sectioning tomography confirmed the extensive distribution of enucleated cells and their reduced entrapment within fibrotic foci. Consequently, enucleated mesenchymal stem cells efficiently deliver mRNA to the fibrotic sites, significantly mitigating pulmonary fibrosis. Our findings provide new insights into the role of enucleation in facilitating cellular transit through constricted vasculature and the underlying mechanobiology of enhanced deformability.