Interference of mRNA therapeutics with cellular microRNA network - implications for effectiveness, long-term outcomes and epigenetic therapy

MicroRNAs like hsa-miR-143-5p play pivotal roles in regulating inflammation, metabolism, and oncogenesis, with emerging significance in SARS-CoV-2 infection and mRNA vaccine interactions. This preliminary study provides the first in silico evidence that the SARS-CoV-2 genome and mRNA-based COVID-19 vaccines (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2) contain conserved „seed” binding sites for hsa-miR-143-5p, a tumor-suppressive miRNA dysregulated in severe COVID-19. Using RNA22 v2, we identified these high-affinity binding sites, suggesting that vaccine mRNA may act as a microRNA „sponge”, potentially sequestering hsa-miR-143-5p as well as other cellular microRNAs. This interaction could reduce antigen expression, contributing to waning vaccine efficacy and even more - vaccine effectiveness, and disrupt hsa-miR-143-5p’s regulation of host genes (e.g., ACE2, NF-κB, TGF-β), exacerbating inflammation and fibrosis in COVID-19. In cancer, hsa-miR-143-5p suppresses oncogenes (KRAS, HK2, BCL-2), and its depletion by vaccine mRNA could derepress oncogenic pathways, potentially increasing cancer risk, particularly in populations with chronic inflammation. These findings highlight a critical oversight in mRNA therapeutic design: off-target microRNA interactions.