The interaction of RNA with biofluids and intracellular proteins has received increased interest in the past decades. Several structural, molecular and functional aspects of this interaction have been clarified and characterised. With the recent arising of RNA-based therapeutics, it has also been highlighted the important contribution that the interaction with protein components has on the pharmacological properties of this new modality. Clarifying and quantifying these binding mechanisms is unanimously considered as an essential factor that could help rationalise the design of any drug formulation containing RNA. The interaction with proteins is a crucial binding event that determines RNA-therapeutics distribution properties, including the one of ligand/nanoparticles used for their delivery. Despite its significance on the overall efficacy of the therapeutic, a lack of methodologies has lagged its understanding. In recent years several academic groups and pharmaceutical companies have taken over the challenge and proposed inventive analytical methods. At Sixfold we apply innovative in vitro and in vivo experimental solutions for the study of RNA/protein interactions and ultimately design our RNA-based delivery system, Mergo. Mergo is a structured and chemically modified RNA scaffold, which is designed for cell-specific distribution of therapeutics. Mergos have shown unique plasma protein binding profiles and signature tissue distributions. The team is currently working on profiling the constructs based on several properties, such as secondary structure, motifs and chemical modifications patterns and on exploring several routes of administrations.