Cell reports methodsSep 16, 2026

Self-amplifying RNA allows fast, lasting, and safe reprogramming of human stem cells

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 17, 2026

Abstract

saRNA delivery enables sustained protein expression in human induced pluripotent stem cells (hiPSCs) for weeks.

Genetic modification of hiPSCs using self-amplifying RNA (saRNA) avoids issues related to traditional genetic engineering methods.
saRNA allows efficient forward programming of hiPSCs into neurons, facilitating long-term measurement of cellular functions.
A single transfection of saRNA-encoded jRCaMP1b leads to persistent expression during differentiation into 3D cardiac spheroids.
This method supports tracking of cardiomyocyte function and drug responses over time.
saRNA provides a potential approach for integration-free cell fate programming in relevant clinical models.

Simplified

Genetic modification of human induced pluripotent stem cells (hiPSCs) is a powerful approach to measure and manipulate cellular processes. Conventional genetic engineering of hiPSCs requires laborious processes involving transfection, selection, and expansion that can cause karyotypic abnormalities or transgene silencing during differentiation. The use of self-amplifying RNA (saRNA) is a potential alternative integration-free method for durable expression of transgenes. Here, we used saRNA to deliver transcription factors and functional reporters in hiPSCs and demonstrated that protein expression can persist for weeks. Specifically, saRNA delivery enabled highly efficient forward programming to Ngn2-induced neurons and measurement of functional reporters over time. We show that a single transfection of saRNA-encoded jRCaMP1b in hiPSCs generates sustained reporter expression throughout differentiation to 3D cardiac spheroids, allowing the tracking of cardiomyocyte function and drug responses. Altogether, our systematic analysis shows that saRNA extends transgene expression in hiPSCs, supporting integration-free cell fate programming and functional reporter measurement in clinically relevant model systems.

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Self-amplifying RNA allows fast, lasting, and safe reprogramming of human stem cells

Abstract

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