Biologically Inspired Design of Nanoparticle Artificial Antigen-Presenting Cells for Immunomodulation

Abstract

Particles engineered to engage and interact with cell surface ligands and to modulate cells can be harnessed to explore basic biological questions as well as to devise cellular therapies. Biology has inspired the design of these particles, such as artificial antigen-presenting cells (aAPCs) for use in immunotherapy. While much has been learned about mimicking antigen presenting cell biology, as we decrease the size of aAPCs to the nanometer scale, we need to extend biomimetic design to include considerations of T cell biology-including T-cell receptor (TCR) organization. Here we describe the first quantitative analysis of particle size effect on aAPCs with both Signals 1 and 2 based on T cell biology. We show that aAPCs, larger than 300 nm, activate T cells more efficiently than smaller aAPCs, 50 nm. The 50 nm aAPCs require saturating doses or require artificial magnetic clustering to activate T cells. Increasing ligand density alone on the 50 nm aAPCs did not increase their ability to stimulate CD8+ T cells, confirming the size-dependent phenomenon. These data support the need for multireceptor ligation and activation of T-cell receptor (TCR) nanoclusters of similar sizes to 300 nm aAPCs. Quantitative analysis and modeling of a nanoparticle system provides insight into engineering constraints of aAPCs for T cell immunotherapy applications and offers a case study for other cell-modulating particles.

Materials for Immunotherapy

“…While some work has been done to use nanoparticles as aAPCs, the majority of examples developed insofar are on the microscale due to their higher efficacy. Clear evidence for this has been demonstrated by Schneck and others . However, designing aAPCs is not trivial.…”

Biomimetic Nanotechnology toward Personalized Vaccines

“…This close proximity increases the probability that both receptors can simultaneously bind to their respective ligands on CTLs, resulting in increased cellular proliferation . Nanoparticle size also plays a similar role, as increases in diameter can tighten the gap between the two signals to promote enhanced interactions with TCRs by providing multivalent binding . However, because larger nanoparticles may exhibit decreased lymphatic drainage, it has been recently demonstrated that decoupling the two signals and including them on different nanoparticles can maximize T cell stimulation while still maintaining the advantages of nanoscale aAPCs .…”

Immunomodulating Nanomedicine for Cancer Therapy

“…This point was further reinforced by a recent study that demonstrated that the sizes of nanoparticles used as substrate for artificial antigen presenting cells is critical in T cell activation. 22 Therefore, if nanoparticle or nanoparticle cluster is below certain threshold size, then even increased ligand density may not be sufficient to properly stimulate a T cell response. 22 …”

“…22 Therefore, if nanoparticle or nanoparticle cluster is below certain threshold size, then even increased ligand density may not be sufficient to properly stimulate a T cell response. 22 …”