Magnetic Manipulation of Reversible Nanocaging Controls in Vivo Adhesion and Polarization of Macrophages

Macrophages are key immune cells that perform various physiological functions, such as the maintenance of homeostasis, host defense, disease progression, and tissue regeneration. Macrophages adopt distinctly polarized phenotypes, such as pro-inflammatory M1 phenotype or anti-inflammatory (pro-healing) M2 phenotype, to execute disparate functions. The remotely controlled reversible uncaging of bioactive ligands, such as Arg-Gly-Asp (RGD) peptide, is an appealing approach for temporally regulating the adhesion and resultant polarization of macrophages on implants in vivo. Here, we utilize physical and reversible uncaging of RGD by a magnetic field that allows facile tissue penetration. We first conjugated a RGD-bearing gold nanoparticle (GNP) to the substrate and then a magnetic nanocage (MNC) to the GNP via a flexible linker to form the heterodimeric nanostructure. We magnetically manipulated nanoscale displacement of MNC and thus its proximity to the GNP to reversibly uncage and cage RGD. The uncaging of RGD temporally promoted the adhesion and subsequent M2 polarization of macrophages while inhibiting their M1 polarization both in vitro and in vivo. The RGD uncaging-mediated adhesion and M2 polarization of macrophages involved rho-associated protein kinase signaling. This study demonstrates physical and reversible uncaging of RGD to regulate the adhesion and polarization of host macrophages in vivo. This approach of magnetically regulating the heterodimer conformation for physical and reversible uncaging of RGD offers the promising potential to manipulate inflammatory or tissue-regenerative immune responses to the implants in vivo.