Magnetic Control of Multiscale Ligand Nanoarchitecture Regulates Stem Cell Fate

Abstract Native tissues exhibit hierarchical structures of anisotropically arranged extracellular matrix that dynamically regulate stem cells and tissue function. However, neither multiscale nano‐anisotropy nor dynamic anisotropy control have been reported. In this study, spherical or rod‐shaped gold small‐nanomaterials (at integrin receptor‐scale; tens of nanometers) are coupled to the surface of spherical or rod‐shaped magnetic large‐nanomaterials (at focal adhesion complex‐scale; hundreds of nanometers), with both showing constant surface areas at each respective scale. Each hierarchical nanocomposite is flexibly conjugated to the substrate material surface at constant densities, resulting in dual‐scale liganded nano‐anisotropies. Increasing the aspect ratio of liganded nanomaterials at the hundreds of nanometer‐scale dominantly promotes integrin recruitment, focal adhesion, mechanotransduction, and differentiation of stem cells over that at the tens of nanometer‐scale. Such scale‐specific liganded nano‐anisotropy effects on stem cell regulation are temporally regulated both in vitro and in vivo by physically raising or lowering hierarchical nanocomposites to respectively inhibit or stimulate stem cell adhesion and differentiation on curved surfaces by modulating cell membrane bending. Such unprecedented “dynamic dual‐scale ligand anisotropy” can be independently engineered regarding material scales, anisotropies, and ligands to elucidate scale‐specific dynamic cell‐material interactions and allow for multimodal stem cell regulation to enhance tissue‐regenerative therapy.