Enabling personalized mRNA therapeutics: the case for platform downstream processing

Personalized mRNA therapeutics demand rapid, sequence-independent manufacturing of clinical-grade material from single-dose batches. Strategies for construct design and in vitro transcription have become more standardized, however downstream processing remains poorly suited to microliter-scale operation, with common methods suffering from sequence/size dependence, toxic solvents, low recovery, or high losses during buffer exchange. This commentary advocates a true integrated small-scale downstream processing (DSP) platform built on oligo(dT) affinity capture followed by a fast flow-through affinity step that selectively removes residual impurities (mainly dsRNA). Implemented on convective supports (monoliths or fibres), this simple two-step, integrated purification train minimizes unit operations, maximizes yield, and is largely sequence-agnostic, ideal for individualized production under regulatory compliance. For large-scale needs, cost-effective alternatives (precipitation, membranes, or continuous oligo(dT) with non-affinity polishing are noted. Standardized, analytically robust DSP platforms are critical to realizing the full potential of personalized mRNA therapeutics.

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