Differences in the immunogenicity of engineered circular RNAs

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Abstract
Circular RNAs (circRNAs) are single-stranded RNAs that are covalently closed and lack free ends. Our current understanding of the functions and regulation of circRNAs in immune systems is still in the nascent stages, but several groups have recently investigated the immunogenicity of engineered circRNAs. However, which factors determine engineered circRNA immunogenicity still remains unclear. Here, we review and compare these investigations on engineered circRNA immunogenicity. We discuss the possible factors that may alter the immunogenic potential of a circRNA, such as its generation, purification, primary sequence, secondary structure, and RNA modifications. We also suggest approaches for designing a circRNA with immunostimulatory or immune-evasive properties and recommend future areas for the field to investigate. Elucidating the factors underlying engineered circRNA immunogenicity is an important step towards understanding endogenous circRNA immunity and increasing the therapeutic potential of circRNAs.

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