Circular RNA in Lipid Nanoparticles: From Molecular Engineering to First-in-Human Testing

Circular RNAs (circRNAs) were, until a decade ago, a by-product of transcriptome profiling. They are now drug candidates. A covalently closed backbone removes the termini that exonucleases and cap-dependent decay require, and lipid nanoparticles (LNPs) turn that molecular property into a pharmacological one by carrying the RNA into the cytoplasm of a chosen cell. Between 2021 and 2026 the field moved from reporter-gene proof of concept to nine first-in-human programmes, five of which encode a CD19 chimeric antigen receptor and one of which has completed. We argue that the central question is no longer whether circRNA can be made and delivered, but which of its claimed advantages survive in vivo, and at what cost in manufacturing complexity. We examine performance determinants at three coupled levels, the molecule, the particle and the biological context, and set out the manufacturing, analytical and regulatory problems that will decide whether circularity becomes a general platform property or a niche solution.