Label-Free Optical Biosensing of Lipid Nanoparticle-mRNA Therapeutics

mRNA vaccines have transformed modern immunotherapy; however, their efficacy and safety critically depend on the accurate design and characterization of lipid nanoparticles (LNPs) that encapsulate and deliver mRNA. Conventional assays, such as dynamic light scattering and fluorescence-based encapsulation measurements, provide key physicochemical metrics but cannot monitor LNP-mRNA interactions in real time. Label-free optical biosensing techniques, including surface plasmon resonance (SPR), biolayer interferometry (BLI), reflectometric interference spectroscopy (RIfS), photonic microring resonators (PMR), and optical waveguide light mode spectroscopy (OWLS), detect refractive index changes or interference patterns without requiring extrinsic labels. In this narrative review, we summarize foundational studies and recent advances to demonstrate how SPR-driven kinetic profiling informs lipid selection, how RIfS and BLI enable high-throughput stability screening, and how photonic microring arrays support multiplexed formulation screening. We also examine innovative applications, such as interferometric monitoring during microfluidic LNP assembly and OWLS-based assays of mRNA accessibility, and present case studies that integrate lipid library screening with continuous manufacturing. Unlike prior reviews that address individual techniques or formulation trends in isolation, this study unifies label-free biosensing modalities across the entire LNP-mRNA life cycle. This study evaluated the throughput, sensitivity, and practical considerations pertinent to both research and industrial environments. We offer researchers and process engineers a detailed framework for selecting and implementing label-free optical biosensors designed to expedite the development, scale-up, and quality control of next-generation RNA therapeutics.