Nanowire Based Mechanostimulating Platform for Tunable Activation of Natural Killer Cells

Abstract

The understanding of the activation mechanism of natural killer (NK) cells has been traditionally based on the biochemical interaction of NK cell receptors with the ligands presenting on target cells. Yet, how physical features of the NK cell environment, such as stiffness and nanoscale topography, regulate the activity of NK cells, is unknown. An artificial microenvironment is developed for NK cell stimulation based on variably elongated nanowires functionalized with activating antigens and used it as a tunable model system to study the separate and cumulative effects of elasticity and nanotopography on NK cell activation. It is found that late signaling, degranulation, and cytokine production in NK cells consistently vary with nanowire length, and it is maximized for the longest nanowires, measuring ≈20 µm in length. Intriguingly, a similar trend is observed for nanowires lacking antigens, albeit with a lower activation magnitude overall, indicating that chemical and mechanical stimuli independently determine the activation of NK cells. The demonstrated tuning of the activation of NK cells by nanoscale physical features of their environment not only provides an important insight into the regulation mechanism of these lymphocytes, but also paves the way to rationally designed nanomaterials for controlled ex vivo activation of NK cells in immunotherapy.

Nanomaterial‐Boosted Tumor Immunotherapy Through Natural Killer Cells

“…[60] Lastly, nanomaterials can mechanically activate NK cells to regulate lymphocytes. [61] These findings pave the way for rational design of antitumor immunotherapies that exploit NK cytotoxicity.…”

Ligand Coupling and Decoupling Modulates Stem Cell Fate

“…The remote manipulation of ligand coupling shown in this study has not been reported in previous studies that modulated only linearly shaped ligands in diverse nano-sequences [48] or nano-patterns, [49] and dynamically modulated only the activation of planarly distributed ligands via UV light, [34] or only the stretching of linearly shaped nano-coiled ligands via a magnetic field. [55] Our materials presenting movably couplable ligands offer the tunability of dimensions, [66][67][68][69] alignment, and bioactive ligands of the MLNs and the dimensions of the AuNPs, [70] which can provide fundamental insight to elucidate the dynamic interplay between ligand coupling and integrin recruitment that modulates stem cell adhesion, mechanosensing, and differentiation.…”

Modulation of Macrophages by In Situ Ligand Bridging

“…[37] Therefore, amongst immune cell types, macrophages can be chosen as master regulators for RGD bridging-and nonbridging-mediated integrin signaling that regulate long-term immune responses to implanted materials. [38][39][40] The arrangement of RGD-coated gold nanospheres (RGD-GNSs) has been constructed in diverse RGD-coated nanogeometries, to represent random network structure. They have been reported to effectively regulate cellular attachment [41] by individually modulating the 2D arrangement of RGD density and inter-RGD nanospacing, [42,43] the inter-RGD nanospacing within a micropattern, [44] localized versus total density, [45] and the degree of clustering.…”

“…[ 37 ] Therefore, amongst immune cell types, macrophages can be chosen as master regulators for RGD bridging‐ and non‐bridging‐mediated integrin signaling that regulate long‐term immune responses to implanted materials. [ 38–40 ]…”