Membranes: The only chance for the mRNA tortoise to win, economically

The RNA revolution, advancing beyond traditional vaccines to new therapeutic modalities and constructs such as self-amplifying RNA (saRNA) and circular RNA (circRNA), continues to place increasing pressure on downstream purification. Diffusion-limited resins, the time-tested workhorse of protein purification, are fundamentally incompatible because mRNA is an enormous (>40 nm) molecule with low diffusivity (10^-11-10^-12 m²/s). Our perspective, rooted in core chemical engineering principles, applies transport analysis and re-examines published performance data to demonstrate why even optimized perfusion chromatographic resin systems, exhibiting 0.1 % of total flow through the resin particles, cannot overcome the inherent diffusional barriers preventing efficient RNA purification. Alternatively, convection-based devices, notably membranes and monoliths, are well situated as their transport characteristics are not limited by the molecular transport properties of RNA. Ultimately, pressure-driven flow enables the potential for increased device capacity at orders of magnitude (10³x) lower process time and smaller device footprint contributing to markedly improved productivity. Taken together, these findings suggest that a paradigm shift is required toward convective membrane systems to create a platform capable of delivering scalable, economic, and ultimately industrially attractive mRNA purification.