Self‐Assembly of Immune Signals to Program Innate Immunity through Rational Adjuvant Design

Abstract

Recent clinical studies show activating multiple innate immune pathways drives robust responses in infection and cancer. Biomaterials offer useful features to deliver multiple cargos, but add translational complexity and intrinsic immune signatures that complicate rational design. Here a modular adjuvant platform is created using self-assembly to build nanostructured capsules comprised entirely of antigens and multiple classes of toll-like receptor agonists (TLRas). These assemblies sequester TLR to endolysosomes, allowing programmable control over the relative signaling levels transduced through these receptors. Strikingly, this combinatorial control of innate signaling can generate divergent antigen-specific responses against a particular antigen. These assemblies drive reorganization of lymph node stroma to a pro-immune microenvironment, expanding antigen-specific T cells. Excitingly, assemblies built from antigen and multiple TLRas enhance T cell function and antitumor efficacy compared to ad-mixed formulations or capsules with a single TLRa. Finally, capsules built from a clinically relevant human melanoma antigen and up to three TLRa classes enable simultaneous control of signal transduction across each pathway. This creates a facile adjuvant design platform to tailor signaling for vaccines and immunotherapies without using carrier components. The modular nature supports precision juxtaposition of antigen with agonists relevant for several innate receptor families, such as toll, STING, NOD, and RIG.

Exploiting Unique Features of Microneedles to Modulate Immunity

“…[ 154 ] This highlights another advantage of model antigen delivery with MNAs: the in vivo effect of adjuvant delivery to APCs can be isolated, contributing to rational design approaches for vaccine adjuvants. [ 155,156 ] Knowledge gained from these studies can be applied to other types of disease models.…”

Harnessing Biomaterials to Study and Direct Antigen-Specific Immunotherapy

“…These studies showed that the ratio of included TLRas dictated levels of corresponding TLR activation and levels of tumor protection in a mouse melanoma model. Interestingly, in a prophylactic vaccine regimen, a vaccine of iPEMs containing a 1:1 ratio of TLR3a:TLR9a with antigen protected mice better than soluble signals or iPEMs containing a single TLRa and antigen (Figure J,K) …”

“…Interestingly, in a prophylactic vaccine regimen, a vaccine of iPEMs containing a 1:1 ratio of TLR3a:TLR9a with antigen protected mice better than soluble signals or iPEMs containing a single TLRa and antigen (Figure 3J,K). 35…”

Harnessing biomaterial architecture to drive anticancer innate immunity

“…[165][166][167] SNAs can incorporate PRR agonists or antagonists for receptor-mediated targeting to bias the innate immune response towards specific phenotypes. 168 SNAs are composed of oligonucleotides arranged radially around a nanoparticle core; they are preferentially taken up compared to free linear oligonucleotides in over 60 cell types due to their multivalent interactions with scavenger receptors on the cell surface resulting in caveolaemediated endocytosis. 169 Hybridized DNA structures (i.e., polypods) that present DNA have also been utilized to increase uptake.…”