Remote Manipulation of Ligand Nano-Oscillations Regulates Adhesion and Polarization of Macrophages in Vivo

Abstract

Macrophages play crucial roles in various immune-related responses, such as host defense, wound healing, disease progression, and tissue regeneration. Macrophages perform distinct and dynamic functions in vivo, depending on their polarization states, such as the pro-inflammatory M1 phenotype and pro-healing M2 phenotype. Remote manipulation of the adhesion of host macrophages to the implants and their subsequent polarization in vivo can be an attractive strategy to control macrophage polarization-specific functions but has rarely been achieved. In this study, we grafted RGD ligand-bearing superparamagnetic iron oxide nanoparticles (SPIONs) to a planar matrix via a long flexible linker. We characterized the nanoscale motion of the RGD-bearing SPIONs grafted to the matrix, in real time by in situ magnetic scanning transmission electron microscopy (STEM) and in situ atomic force microscopy. The magnetic field was applied at various oscillation frequencies to manipulate the frequency-dependent ligand nano-oscillation speeds of the RGD-bearing SPIONs. We demonstrate that a low oscillation frequency of the magnetic field stimulated the adhesion and M2 polarization of macrophages, whereas a high oscillation frequency suppressed the adhesion of macrophages but promoted their M1 polarization, both in vitro and in vivo. Macrophage adhesion was also temporally regulated by switching between the low and high frequencies of the oscillating magnetic field. To the best of our knowledge, this is the first demonstration of the remote manipulation of the adhesion and polarization phenotype of macrophages, both in vitro and in vivo. Our system offers the promising potential to manipulate host immune responses to implanted biomaterials, including inflammation or tissue reparative processes, by regulating macrophage adhesion and polarization.

Anisotropic Nanoscale Presentation of Cell Adhesion Ligand Enhances the Recruitment of Diverse Integrins in Adhesion Structures and Mechanosensing‐Dependent Differentiation of Stem Cells

“…Beside, it has been demonstrated that RGD‐conjugated rod‐like viral nanoparticles coated on substrates promoted the osteogenesis . We previously achieved magnetic control over the tether mobility of RGD peptide‐bearing magnetic nanoparticles conjugated to substrates through flexible poly(ethylene) glycol linkers, and this manipulation of the nanoscale presentation of the cell adhesive ligand by nanomaterials regulates the adhesion and differentiation of stem cells and polarization of macrophages . Nevertheless, few studies have investigated the effects and mechanism of anisotropic nanofeature‐mediated recruitment, and the distribution of different integrin subtypes of cells is an important missing link in elucidating the molecular interactions between cells and nanomaterials.…”

Recent Advances in Magnetic‐Nanomaterial‐Based Mechanotransduction for Cell Fate Regulation

“…Except for regulating stem cells, MN‐based strategy can also manipulate the function of other cell types, including macrophages, Chinese hamster ovary (CHO) cells, cochlear hair cells, and cortical neurons . Bian and co‐workers reported that MNs‐RGD with a diameter <20 nm were able to manipulate macrophage adhesion and polarization via delivering oscillation toward cell membrane .…”

“…Except for regulating stem cells, MN‐based strategy can also manipulate the function of other cell types, including macrophages, Chinese hamster ovary (CHO) cells, cochlear hair cells, and cortical neurons . Bian and co‐workers reported that MNs‐RGD with a diameter <20 nm were able to manipulate macrophage adhesion and polarization via delivering oscillation toward cell membrane . Magnetic oscillation of low‐frequency MNs‐RGD enhanced adhesion of macrophages and stimulated polarization toward the M2 phenotype whereas under a high oscillation frequency, macrophages tended to be less adhesive and polarized to the M1 phenotype …”

“…Bian and co‐workers reported that MNs‐RGD with a diameter <20 nm were able to manipulate macrophage adhesion and polarization via delivering oscillation toward cell membrane . Magnetic oscillation of low‐frequency MNs‐RGD enhanced adhesion of macrophages and stimulated polarization toward the M2 phenotype whereas under a high oscillation frequency, macrophages tended to be less adhesive and polarized to the M1 phenotype …”

Dynamic substrates for cell biology

“…Indeed, the Bian group reported the successful modulation of adhesion and polarization with magnetically responsive substrates implanted in mice. [45••–46]…”