A Hypothetical Framework for Genotoxic and Proteotoxic Risk via Covalent Lipid and Nucleic Acid Adduct Formations in mRNA LNP Vaccines

Adductomics is the systematic study of covalent modifications to biomolecules, providing a framework for evaluating potential biological concerns in pharmaceuticals. Historical precedents, including withdrawals of medications like fialuridine and troglitazone, demonstrate that even low frequency adduct formation can lead to genotoxic or proteotoxic events. Recent Moderna funded research found that cationic and ionizable lipid nanoparticles can form covalent adducts with modified RNA nucleotides under assay conditions, with adduct levels increasing at physiological temperatures approaching those of the human body. These findings raise the hypothesis that in vivo environments--characterized by 37 °C, complex ionic composition, reactive oxygen species, dynamic zeta potential, and persistence of synthetic RNA for weeks--could amplify the frequency or diversity of these adducts. Reactive lipids could also theoretically bind residual linearized plasmid DNA contaminants in COVID or other vaccines, or interact with endogenous nucleic acids, introducing pathways for covalent modifications that may alter nuclear DNA interactions, RNA, chromatin structure, proteins, and protein associations. These considerations underscore the need for proper systematic adductomic, proteomic, and genotoxicity testing of RNA lipid nanoparticle therapeutics to evaluate potential in vivo risks before continued clinical deployment.