A Predictive In Vitro Platform for Comprehensive Assessment of Lipid Nanoparticle Performance

Lipid nanoparticles (LNPs) have become a cornerstone technology in modern drug delivery, particularly in the development of mRNA vaccines and nucleic acid-based therapies. Their ability to efficiently encapsulate and transport a range of therapeutic payloads—including mRNA, siRNA, and small molecules—has enabled breakthroughs in infectious disease prevention and gene modulation strategies. However, the clinical success of LNPs hinges not only on their delivery efficiency, but also on their immunological profile. Activation of the innate immune system by LNPs can influence both therapeutic efficacy and safety, making it critical to assess immune responses early during development.

A major challenge in the field is the lack of predictive, scalable, and reproducible in vitro models to evaluate innate immune activation triggered by diverse LNP formulations. Currently, the most commonly used systems rely on primary human immune cells, such as peripheral blood mononuclear cells (PBMCs). While these models can provide insight into cytokine induction and inflammatory signaling, they are inherently limited by donor-to-donor variability, inconsistent sensitivity, and limited scalability. These limitations hinder robust comparative analyses of formulation parameters and reduce confidence in the translation of in vitro findings to in vivo outcomes. To overcome these issues, our efforts have focused on developing more standardized immune cell platforms that maintain physiological relevance while offering greater consistency across experiments. These platforms aim to support screening of LNPs with different physicochemical characteristics. In testing, some of these emerging platforms have demonstrated improved reproducibility and sensitivity compared to PBMC-based assays. When applied to LNPs designed with varying immunogenic profiles, these models have shown the ability to distinguish between high-, moderate-, and low-activation formulations.

In summary, the development and application of improved in vitro immune profiling platforms represent a critical step toward safer and more effective LNP-based therapies. These systems provide a promising avenue for enhancing formulation design, de-risking clinical candidates, and ultimately translating lipid nanoparticle technologies into impactful medicines.