Hitching a Ride to Overcome Barriers: Nonclinical Safety Considerations for Bioconjugated Oligonucleotides

Advances in the delivery and safety of nucleic acid-based therapeutics are enabling tissue-selective targeting and broadening the reach of genetic medicines. In addition to GalNAc-conjugated oligonucleotides, newer modalities-predominantly antibody- and peptide-conjugated oligonucleotides-combine innovative components with complex and often multimodal mechanisms of action. These constructs may require tailored nonclinical testing strategies to evaluate pharmacology, biodistribution, and component- and construct-driven toxicities. Here, we review the current state of these molecules, collectively termed here as bioconjugated oligonucleotide (BCO) therapeutics, summarize key safety liabilities across the protein scaffold, linker, and oligonucleotide payload, and highlight nonclinical approaches, including predictive safety assessments and in vivo toxicity studies that can support human clinical trials. We also discuss risk-based regulatory considerations that may differ from traditional biologics or small molecules.