Remote Manipulation of Slidable Nano‐Ligand Switch Regulates the Adhesion and Regenerative Polarization of Macrophages

The development of materials capable of varying macroscale ligand distributions can emulate an extracellular matrix (ECM) remodeling and regulate the adhesion and polarization of macrophages. In this report, negatively charged slidable nano‐ligands are assembled and then conjugated to a positively charged substrate via electrostatic interaction. The negatively charged slidable nano‐ligands are prepared by coating magnetic nanoparticles with a polymer linker and negatively charged RGD ligand. The nano‐ligand sliding is characterized under an external magnetic field, which spatiotemporally alters macroscale ligand density. To the best of knowledge, this is the first demonstration that magnetic maipulation of the macroscale ligand density inhibits inflammatory M1 phenotype but stimulates the adhesion and regenerative M2 phenotype of host macrophages. Furthermore, it is elucidated that the magnetic attraction of the slidable nano‐ligand facilitates the assembly of adhesion structures in macrophages, thereby stimulating their regenerative M2 phenotype. The design of ECM‐emulating materials that allow remote, spatiotemporal, and reversible controllability of macroscale ligand density provides an appealing strategy in the spatiotemporal regulation of immunomodulatory tissue‐regenerative responses to implants in vivo.     

Remote Switching of Elastic Movement of Decorated Ligand Nanostructures Controls the Adhesion-Regulated Polarization of Host Macrophages

Design of materials with remote switchability of the movement of decorated nanostructures presenting cell-adhesive Arg-Gly-Asp ligand can decipher dynamic cell-material interactions in decorated ligand nanostructures. In this study, the decoration of ligand-bearing gold nanoparticles (ligand-AuNPs) on the magnetic nanoparticle (MNP) with varying ligand-AuNP densities is demonstrated, which are flexibly coupled to substrate in various MNP densities to maintain constant macroscopic ligand density. Magnetic switching of upward (“Upper Mag”) or downward (“Lower Mag”) movement of varying ligand-AuNPs is shown via stretching and compression of the elastic linker, respectively. High ligand-AuNP densities promote macrophage adhesion-regulated M2 polarization that inhibits M1 polarization. Remote switching of downward movement (“Lower Mag”) of ligand-AuNPs facilitates macrophage adhesion-regulated M2 polarization, which is conversely suppressed by their upward movement (“Upper Mag”), both in vitro and in vivo. These findings are consistent with human primary macrophages. These results provide fundamental understanding into designing materials with decorated nanostructures in both high ligand-AuNP density and downward movement of the ligand-AuNPs toward the substrate to stimulate adhesion-regulated M2 polarization of macrophages while suppressing pro-inflammatory M1 polarization, thereby facilitating tissue-healing responses.     

Stimuli‐Free Reversible and Controllable Loading and Release of Proteins under Physiological Conditions by Exponentially Growing Nanoporous Multilayered Structure

A unique delivery system to reversibly and controllably load and release proteins under physiological conditions is desirable for protein therapeutics. We fabricate an ultrafast exponentially growing nanoporous multilayer structure comprised of two weak polyelectrolytes, poly(ethyleneimine) and alginate with thickness and chemical composition controlled by the assembly pH. For the first time, the assembled multilayered structure demonstrates stimuli‐free reversible protein loading and release capability at physiological conditions by a synthetic material. The protein loading and release time can also be controlled by the assembled bilayer number. The highest loading capacity for the target protein and longest release time of proteins for layer‐by‐layer films reported to date have been achieved with a 15‐bilayered film fabricated in this work. The prominent properties of the assembled film provide great potential for various biomedical applications, especially as a delivery system for protein therapeutics.