The Power of Three: Nanomaterials for Natural Killer (NK) Cell Immunoengineering Maximize Their Potency if They Exploit Multireceptor Stimulation

Abstract

AbstractMany emerging cancer treatments are immunotherapies that modulate Natural Killer‐ (NK) or T cell activation, posing a challenge to develop immunoengineering nanomaterials that improve on the performance of molecular reagents. In physiological activation, multiple immunoreceptors signal in consort; however, current biomaterials do not replicate this. Here, NK cells are created for the first time, activating bionanomaterials that stimulate >2 immunoreceptors. Nanoclusters of monoclonal antibodies (mAb), templated by nanoscale graphene oxide sheets (NGO) (≈75 nm size), are exploited. To inform nanoreagent design, a model system of planar substrates with anchored mAb is first investigated. Combining mAb that stimulates three NK cell activating receptors (αNKP46 + αNKG2D + αDNAM‐1), activated NK cells act more potently than any single receptor or pair. Applying this insight, an NGO‐mAb nanocluster combining three distinct mAb: NGO‐mAb(αNKP46 + αNKG2D + αDNAM‐1) is created. This construct is potent and outperforms single‐receptor‐simulating nanoclusters, activating nearly twice as many NK cells as NGO‐mAb(αNKP46) at a similar mAb dose or delivering similar activation at 10× lower dosage. Further, NGO‐mAb are more potent than planar substrates for both single‐ and triple‐mAb stimulation. These results imply a new concept for immunoengineering biomaterials: both nanoclustering and multi‐receptor stimulation should be incorporated for maximum effect.