Toll-Like Receptor-Mediated Recognition of Nucleic Acid Nanoparticles (NANPs) in Human Primary Blood Cells.

Enping Hong,Kirill Afonin,Justin Halman,Ankit Shah,Edward Cedrone,Marina Dobrovolskaia,Nguyen Truong

doi:10.3390/molecules24061094

Abstract

Infusion reactions (IRs) create a translational hurdle for many novel therapeutics, including those utilizing nanotechnology. Nucleic acid nanoparticles (NANPs) are a novel class of therapeutics prepared by rational design of relatively short oligonucleotides to self-assemble into various programmable geometric shapes. While cytokine storm, a common type of IR, has halted clinical development of several therapeutic oligonucleotides, NANP technologies hold tremendous potential to bring these reactions under control by tuning the particle’s physicochemical properties to the desired type and magnitude of the immune response. Recently, we reported the very first comprehensive study of the structure–activity relationship between NANPs’ shape, size, composition, and their immunorecognition in human cells, and identified the phagolysosomal pathway as the major route for the NANPs’ uptake and subsequent immunostimulation. Here, we explore the molecular mechanism of NANPs’ recognition by primary immune cells, and particularly the contributing role of the Toll-like receptors. Our current study expands the understanding of the immune recognition of engineered nucleic acid-based therapeutics and contributes to the improvement of the nanomedicine safety profile.

Highlights

Infusion reactions (IRs) are common adverse effects of a variety of drug products
peripheral blood mononuclear cells (PBMC) were chosen as a model for this study because they accurately represent the immune response of humans, are more sensitive to cytokine-mediated toxicities than in vivo preclinical studies in non-human primates and rodents, and are often referred to as the best model to identify cytokine-mediated toxicities during translational studies of novel therapeutics [37,38,39,40,41]
Since plasmacytoiddendritic dendriticcells cells (pDCs) express two endosomal Toll-like receptors (TLR), namely TLR7 and TLR9 [6], and our earlier study in reporter-cell lines suggested the involvement of these TLRs in NANPs recognition [33], we focused on these TLRs for the subsequent detailed analysis

Summary

Introduction

Infusion reactions (IRs) are common adverse effects of a variety of drug products. The underlying causes are incompletely understood and involve many mechanisms. The common and best understood mechanisms of IRs to nanotechnology-formulated products are complement activation-related pseudoallergy (CARPA) and cytokine storm syndrome (CSS). These adverse effects require timely and accurate assessment and intervention. IRs may be fatal [1]. Excessive production of cytokines alters the regulation of inflammation and may lead to systemic response and organ damage. The clinical manifestations of CSS include erythematous or purpuric rash, tachypnea, generalized swelling, hypotension, fever, altered mental status, diffuse lymphadenopathy, malaise, tachycardia, and enlargement of liver and spleen [2]

Methods

Results

Conclusion