Red blood cells could protect miRNAs from degradation or loss thanks to Argonaute 2 binding.

Red blood cells (RBCs) have emerged as reservoirs of microRNAs (miRNAs) in the circulatory system, challenging the traditional view of their nucleic acid absence. This study investigates the miRNA profiles and stability of both native and engineered RBCs. We demonstrate that RBCs are rich in miRNAs, which remain stable under physiological conditions, likely due to their association with Ago2, a key RNA-binding protein. The stability and retention of miRNAs persist even after hypotonic dialysis used for RBC engineering. These findings underline the potential of RBCs as miRNA carriers for therapeutic applications and as a foundation for RNA-based delivery systems. Such advancements could redefine their role in transfusion medicine and advanced RNA therapies.