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Tissue-Specific Silencing of Synthetic mRNAs By De-Targeting Elements Maps Vaccination-Competent Tissues, and Allows Cas9 De-Immunization
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DOI：10.1016/j.ymthe.2026.07.050.png)
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Abstract
En 中文
The clinical success of mRNA/LNP-based vaccines has established a leading platform for in vivo nucleic acid delivery, yet the relationship between biodistribution, tissue-specific translation, and immune activation remains poorly defined. Here, we systematically investigate the anatomical determinants of immune responses elicited by mRNA/LNPs. Using a gold-standard LNP formulation, we map exogenous mRNA biodistribution and functionally interrogate the contribution of distinct organs to both humoral and cellular immunity. To achieve this, we engineered mRNAs containing 3'-UTR embedded de-targeting elements as target sites for endogenous tissue-specific microRNAs, enabling selective silencing of antigen expression in defined anatomical compartments. This approach allowed us to causally link sites of translation with immune outputs. Applying this strategy to a Spike-based vaccine model, we identify muscle and spleen as the most immunologically competent tissues required for robust immune priming. These findings provide a framework for the rational design of next-generation mRNA/LNP formulations with enhanced targeting precision, enabling dose sparing and reduced off-target effects. Furthermore, we extended this concept to genome editing by preventing mRNA-Cas9 expression in immune active tissues, thereby reducing its immunogenicity and toxicity. Collectively, our work establishes a unifying strategy to optimize both potency and safety of mRNA-based therapeutics.
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