Pharmacological reprogramming of macrophages through aptamiRs

Abstract

Nucleic acid-based molecules have certain advantages over conventional drugs or protein-based target approaches. Chemically synthetized nucleic acids-based molecules are known as aptamers. They are selected from a combinatorial oligonucleotide library in a unique way called "SELEX" (systematic evolution of ligands by exponential enrichment). These are single-stranded oligonucleotides with specific three-dimensional configuration. They can be bound to their specific target with high affinity and specificity. Recently, aptamers targeting mammalian cells have emerged as potential candidates for use as delivery vehicles. Numerous therapeutic agents including miRNA, siRNA, peptides, proteins, nanoparticles, and chemotherapeutics can be delivered into the cells via cell-targeting aptamers. <br /> Macrophages and dendritic cells (DCs) play a vital role in the immune response. These cells are involved in physiological and pathological processes in the body. DCs are considered to be one of the most potent ―professional‖ antigen presenting cells (APCs) and have the properties to present endogenous or foreign antigens on their surfaces for the activation of T cells. Therefore, DC-based vaccines designed for activation and proliferation of T cells have significant immunotherapy-related importance. On the other side, macrophages play a key role in different diseases including chronic inflammation. miRNA 125a-5p is highly upregulated in chronic inflammatory macrophages and may have an impact on the polarization of macrophages or on the condition of the disease. In the current study, it was explored that an aptamer targeting immune cells could be used as a delivery vehicle. Herein, Next generation sequencing (NGS) data of murine bone marrow-derived DCs cell-SELEX was used to identify a promising aptamer targeting macrophages and DCs. DC 12 aptamer has been identified and characterized as a promising and suitable delivery vehicle. It has been shown that DC 12 aptamer is non-immunogenic and internalizes into the cells.<br /> The study found that DC 12 aptamer guided uptake of antagomir 125a-5p may end up in the endosomal compartment of macrophages, thereby limiting its inhibitory effect. However, DC 12 has the potential to deliver OT-I peptide into the desired processing compartment of BM-DCs for the targeted activation of CD8 T cells. In summary, aptamers have the potential to replace other carrier molecules, but further investigation will be needed as regards the delivery of the cargo into the cell cytoplasm.