A risk-based framework to guide oversight of nucleic acid constructs

Existing nucleic acid synthesis screening guidance refers broadly to nucleic acids and their constructs, leaving providers and policymakers uncertain which products warrant biosecurity oversight. This uncertainty can lead to gaps in protection if risky products are ungoverned, and unnecessary burdens on legitimate biological research if products that pose negligible risk are governed. This Perspective article presents a risk-informed framework for classifying synthetic nucleic acid products based on their biosecurity relevance to inform proportionate screening guidance. Drawing on input from specialists in synthetic biology and biosecurity, we developed a three-tier classification of synthetic nucleic acids, which distinguishes custom from non-custom products and groups them into high-, intermediate-, and low-risk categories. The framework suggests that the strictest scrutiny should apply to longer DNA and RNA sequences (≥50 bp/nt), including custom orders, regardless of their source, and non-custom products derived from potential pandemic viruses or other viruses regulated under the Federal Select Agent Program. Very short oligonucleotides (<30 bp/nt) and non-DNA/RNA nucleic acids should likely be excluded from routine screening. The framework also defines an intermediate-risk category for products that lie between these length thresholds or that incorporate nucleic acids into medical or other products, as these cases require further investigation and policy development. Our assessment also identifies materials not clearly covered by current guidelines as requiring oversight, such as long viral sequences in non-custom repositories. We highlight these evidence gaps and areas for investigation, and describe how this framework can help align synthesis screening oversight with the most significant biological risks.