Rethinking modRNA Immunogenicity: Toward a Human Genotype-Guided PRR/ISR Atlas

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Abstract
In vitro-transcribed modified mRNA is a promising platform for transient protein replacement in regenerative medicine, including cardiomyocyte regeneration, but repeated dosing is limited by variable innate immune activation and ISR-mediated translation shutdown across individuals. We propose a Human-specific PRR/ISR Immunogenicity Atlas: a focused, genotype-aware computational framework linking patient genetic variation in pattern recognition receptors and ISR components to predict immune and translation responses for IVT modRNA. The Atlas generates individualized “genetic passports” that stratify responder risk, estimate cytokine and PKR/eIF2α activation, and prioritize clinically feasible temporary knockdown strategies (LNP-siRNA/ASO or small molecules). We outline a six-stage roadmap covering data integration, feature engineering, multi-modal modeling, uncertainty quantification, a knockdown prioritization module, and open deployment. Ethical, privacy, ancestry-representation, and regulatory considerations are discussed, along with a staged validation strategy. This Atlas provides a conceptual and practical framework to support safer, more consistent protein replacement in regenerative medicine by moving from one-size-fits-all to genotype-guided approaches.

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