Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Abstract

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo⁺ self-assembly composed of azobenzene derivatives (Azo⁺) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces <i>cis</i>-Azo⁺-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both <i>in vitro</i> and <i>in vivo</i>, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo⁺ molecules and loaded molecules. Conversely, visible light induces <i>trans</i>-Azo⁺ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term <i>in vivo</i> stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.