Small non-coding RNAs encapsulating mammalian cells fuels innate immunity

Our study addresses the void in understanding surface RNAs, notably glycan-RNAs, abundant on the cell exterior yet lacking precise mapping, particularly in rare cell populations. We present AMOUR, a technique uniting RNA capture with T7-based linear amplification, facilitating accurate profiling of surface RNAs while maintaining plasma membrane integrity. Validation via surface fluorescence in-situ hybridization and RNA aptamer imaging confirms their presence on the outer membrane, autonomously associating in vitro, independent of protein scaffolding. Our work reveals non-coding RNAs as integral components of diverse human and murine hematopoietic cell surface RNAs. Single-cell sequencing of human umbilical cord blood mononuclear cells identifies prevalent Y RNAs on monocyte surfaces. Notably, these Y RNAs interact with histones, critically regulating interleukin-6 (IL-6) gene expression and subsequent protein secretion upon histone stimulation. Highlighting the pivotal role of Y RNAs, our findings clarify their involvement in innate immune activation by capturing and presenting extracellular histones.