Targeting Tumor Necrosis Factor Receptor 1 with Selected Aptamers for Anti-Inflammatory Activity

Tumor necrosis factor-alpha (TNF alpha) inhibitors are widely used in treating autoimmune diseases like rheumatoid arthritis (RA). These inhibitors can presumably alleviate RA symptoms by blocking TNF alpha-TNF receptor 1 (TNFR1)-mediated pro-inflammatory signaling pathways. However, the strategy also interrupts the survival and reproduction functions conducted by TNF alpha-TNFR2 interaction and causes side effects. Thus, it is urgently needed to develop inhibitors that can selectively block TNF alpha-TNFR1 but not TNF alpha-TNFR2. Here, nucleic acid-based aptamers against TNFR1 are explored as potential anti-RA candidates. Through the systematic evolution of ligands by exponential enrichment (SELEX), two types of TNFR1-targeting aptamers were obtained, and their KD values are approximately 100-300 nM. In silico analysis shows that the binding interface of aptamer-TNFR1 highly overlapped with natural TNF alpha-TNFR1 binding. On the cellular level, the aptamers can exert TNF alpha inhibitory activity by binding to TNFR1. The anti-inflammatory efficiencies of aptamers were assessed and further enhanced using divalent aptamer constructs. These findings provide a new strategy to block TNFR1 for potential anti-RA treatment precisely.