Nanoparticle-enabled tuning of cell density for enhanced adhesion and tissue repair

Low retention of transplanted stem cells at target sites remains a major barrier to the clinical translation of cell-based therapies. Conventional strategies, including genetic modification, chemical functionalization, and biomaterial encapsulation, often face limitations in translational feasibility, safety, or procedural complexity. Here, we present a nanoparticle-enabled biophysical approach to enhance cell retention. We incorporate cell-settling nanoparticles composed of clinically approved materials into mesenchymal stem cells, increasing cellular density to accelerate gravitational settling and improve adhesion and survival. Building on this, we develop copper-chaperone-activatable nanoparticles, which enhance tissue regeneration and anti-fibrotic signaling through activation of fibroblast growth factor 2 and a positive feedback loop. In a mouse skin wound model, we show that copper-chaperone-activatable nanoparticle-treated mesenchymal stem cells exhibit enhanced vascularization and reduced fibrosis. These findings demonstrate that modulation of cellular density and physical forces can improve stem cell engraftment, establishing a biophysical framework for safe and translationally relevant cell-based therapies.