Scientists of the University of Bonn and Stanford University have discovered that mammalian IRES-like sequences can overcome the efficiency limitations of eukaryotic translation initiation in circular RNA therapeutics. This breakthrough technology could transform RNA-based therapeutics by allowing sustained protein expression from stable circular RNA, with applications ranging from cancer treatment to enzyme replacement therapy and RNA-based vaccines. IRES (Internal Ribosome Entry Site) sequences are crucial for initiating protein translation in circular RNA, but current solutions rely heavily on viral sequences which pose significant limitations for therapeutic applications. While eukaryotic IRES-like sequences offer a safer alternative, their efficiency has traditionally been much lower than their viral counterparts. Particularly interesting are the IRES-like sequences found in Hox genes, which play critical roles in tissue development through their precise spatiotemporal expression patterns. The development of effective non-viral IRES sequences for circular RNA could provide a new path forward for long-term protein delivery in diseases requiring sustained therapeutic protein expression. IRES-like sequences from mouse Hox genes enabled highly efficient cap-independent translation in circular RNA constructs. These sequences demonstrated superior translation efficiency compared to other eukaryotic IRES sequences, while maintaining the safety advantages of non-viral elements. Importantly, the system allows for fine-tuned protein expression through targeted 2-4 nucleotide mutations in the IRES-like sequences, enabling precise control over generated therapeutic protein levels.