Self-amplifying RNA and circular RNA vaccines: mechanisms, delivery strategies, and prospects for long-lasting immunity.

Messenger RNA vaccines have demonstrated extraordinary success during the COVID-19 pandemic, yet conventional mRNA platforms exhibit inherent limitations including modest molecular stability, stringent cold-chain requirements, waning antibody responses, and the necessity for relatively high doses to achieve protective immunity. Next-generation RNA technologies-specifically self-amplifying RNA (saRNA) and circular RNA (circRNA) vaccines-address these shortcomings through fundamentally distinct molecular designs that enhance antigen expression kinetics and prolong immunological persistence. Self-amplifying RNA vaccines incorporate viral replicase elements derived from alphaviruses, enabling intracellular amplification of the antigen-encoding sequence and sustained protein production at doses substantially lower than conventional mRNA. Circular RNA vaccines feature covalently closed loop structures that confer complete resistance to exonuclease-mediated degradation, extending translational half-life and maintaining antigen presentation over extended periods. This review provides a comprehensive examination of the molecular architecture, intracellular processing mechanisms, and immune activation pathways characteristic of both platforms. We critically evaluate formulation and delivery strategies, with particular emphasis on lipid nanoparticles and emerging carrier systems, and assess manufacturing challenges related to scalability, purity, and quality control. The preclinical and early clinical evidence supporting both platforms is synthesized and compared, highlighting the dose-sparing capacity of self-amplifying RNA and the exceptional durability of circular RNA-induced responses. Persistent obstacles-including reactogenicity modulation, circularization efficiency, replicase-associated innate suppression, and regulatory standardization-are analyzed in depth. We conclude by identifying priority research directions essential for clinical translation, including optimized delivery systems, refined safety profiling, and cold-chain-independent formulations that will enable global vaccine accessibility.