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 clinical translation. 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. Cell-settling nanoparticles (CN), composed of clinically approved materials, are rapidly incorporated into mesenchymal stem cells (MSCs), increasing cellular density to accelerate gravitational settling and improve adhesion and survival. Building on this, we develop copper-chaperone-activatable nanoparticles (CCN), which enhance tissue regeneration and anti-fibrotic signaling through activation of fibroblast growth factor 2 (FGF2) and a positive feedback loop. In a mouse skin wound model, CCN-treated MSCs 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.