Manipulating Nanoparticle Aggregates Regulates Receptor–Ligand Binding in Macrophages

Abstract

The receptor−ligand interactions in cells are dynamically regulated by modulation of the ligand accessibility. In this study, we utilize size-tunable magnetic nanoparticle aggregates ordered at both nanometer and atomic scales. We flexibly anchor magnetic nanoparticle aggregates of tunable sizes over the cell-adhesive RGD ligand (Arg-Gly-Asp)-active material surface while maintaining the density of dispersed ligands accessible to macrophages at constant. Lowering the accessible ligand dispersity by increasing the aggregate size at constant accessible ligand density facilitates the binding of integrin receptors to the accessible ligands, which promotes the adhesion of macrophages. In high ligand dispersity, distant magnetic manipulation to lift the aggregates (which increases ligand accessibility) stimulates the binding of integrin receptors to the accessible ligands available under the aggregates to augment macrophage adhesion-mediated pro-healing polarization both in vitro and in vivo. In low ligand dispersity, distant control to drop the aggregates (which decreases ligand accessibility) repels integrin receptors away from the aggregates, thereby suppressing integrin receptor− ligand binding and macrophage adhesion, which promotes inflammatory polarization. Here, we present "accessible ligand dispersity" as a novel fundamental parameter that regulates receptor−ligand binding, which can be reversibly manipulated by increasing and decreasing the ligand accessibility. Limitless tuning of nanoparticle aggregate dimensions and morphology can offer further insight into the regulation of receptor−ligand binding in host cells.

Mechanical stimuli-driven cancer therapeutics

“…Compression and tension can be vertically exerted on cell membranes or organelles by the MNMs in any shape, including magnetic nanospheres under the SMF and PMF, while the MNMs in sharper shape can apply higher compression on cells that are more cell-penetrative. 60,61,69 The rubbing effect (shear force and compression) can be laterally applied to cell membranes or organelles by the MNMs under the OMF, AMF, and RMF. 70 The spin and rotation about a point of the MNMs arise from the rotation of their magnetic spin and moment ( μ ) to directionally align themselves with the changing external magnetic field (B).…”

“…5a). [60][61][62][63][64] The AMF flips the magnetic field direction while the RMF rotates the magnetic field direction. Hence, magnetic field modes can be selected for the required mechanical motion to enable precise cancer therapy.…”

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

“…218 Moreover, active surface modifications with sufficiently accessible ligands enhance selective targetability of nanomedicines towards tumor cells or tumorassociated macrophages. 219,220 In one study, surface modification of glucose moieties in generation 4 hydroxyl PAMAM dendrimers endowed them with the targetability towards TAMs via interaction between glucose and glucose transporters. Meanwhile, replacement of glucose with galactose facilitated targeting galactins on the surface of glioblastoma cells.…”

Multifunctional Magnetic Nanoparticles for Dynamic Imaging and Therapy

“…[ 106 ] Magnetic aggregates exhibiting various ligand dispersion were harnessed for immunoregulation. [ 107 ] In this system, the ligand accessibility of macrophages was enhanced or suppressed with the magnetic lifting or dropping of the MNP clusters, respectively. The increased ligand accessibility resulted in regenerative macrophage polarization with higher macrophage adhesion and decreased ligand accessibility resulted in inflammatory polarization with lower macrophage adhesion.…”