The hidden half of lipid nanoparticle manufacturing: Downstream processing

Lipid nanoparticles (LNPs) are the dominant nonviral delivery platform for nucleic acid therapeutics, yet their manufacturing remains complex and difficult to scale reproducibly. Downstream operations, particularly membrane-based unit operations such as buffer exchange and sterile filtration, are central determinants of LNP manufacturability but remain comparatively underrepresented in the academic literature relative to upstream particle formation. This Review demonstrates that downstream processing actively reshapes critical product quality attributes, including particle size, morphology, internal structure, payload distribution, and stability. Each downstream unit operation imposes distinct physicochemical perturbations that collectively determine the final drug product. Many of these changes are formulation-dependent and directly influence biological performance. We identify key knowledge gaps in analytical technologies, mechanistic understanding, and process development practices, and argue that robust LNP manufacturing requires upstream and downstream operations to be designed as a single, coupled process.