Nucleic Acid Nanoparticles Redefine Traditional Regulatory Terminology: The Blurred Line between Active Pharmaceutical Ingredients and Excipients

Abstract

Nucleic acid nanoparticles (NANPs) make up a structurally heterogeneous class of nanosized architectures that self-assemble from rationally designed oligonucleotides via canonical and noncanonical base-pairing. Over the past decade, extensive research and development have advanced NANP technologies, bringing them closer to clinical settings. Notably, several functional nucleic acid components, integral to NANPs, have already received regulatory approval for therapeutic use. The successful translation of NANPs requires a comprehensive understanding of not only their key quality attributes but also the definitions established by regulatory health agencies, as such classification helps apply an appropriate regulatory framework to ensure successful clinical translation. A critical analysis of current knowledge about NANPs in the context of regulatory definitions reveals that NANPs can serve as active pharmaceutical ingredients (APIs) and excipients and can even combine both functions simultaneously, depending on their intended therapeutic mechanism of action and formulation context. This dual-role capacity is relatively unique among pharmaceutical materials, as most current materials serve as either an API or an excipient. Moreover, the potential for conditional activation of therapeutic functions for NANPs designed to become biologically active only in specific physiological environments adds a further layer of complexity to their regulatory classification.