Melting point matters: designing lipid nanocarriers for improved T cell activation

Surface-modified lipid nanocarriers are increasingly used as artificial antigen-presenting cells for therapeutic applications in immunotherapy. Within these nanocarriers, the role of the lipids is typically limited to providing structure/stability of the particle, to anchoring a targeting moiety, and/or to altering the biodistribution of the nanocarriers <i>in vivo</i>. However, lipid membranes also possess special thermodynamic properties that impact their function. Here, we investigate the effect of the melting transition temperature of lipid nanocarriers on the activation efficiency of an immortalized line of T lymphocytes. Using an established <i>in vitro</i> activation assay and αCD3-functionalized lipid nanocarriers, we screened a variety of lipid nanocarriers with respect to their capacity to activate T cells. We observed a correlation between T cell activation efficiency and proximity of the melting transition temperature of the lipid nanocarrier to the temperature at which the activation study was conducted (37 °C). This relationship held across a variety of lipid compositions and appeared to be more important than the lipid headgroup or chain length. This trend was preserved when the activation temperature was shifted to 30 °C, supporting the role of the nanocarrier membrane state for target cell activation and the potential impact of phase-transition-related effects on nanocarrier activity. We conclude that lipid composition is indeed an important parameter for lipid-based nanocarrier design, not only for the more explored biochemical roles of the lipids but also for the thermodynamic properties the lipid mixtures generate. Our results provide a new consideration in therapeutic nanocarrier design that could significantly improve the efficacy of targeted nanocarrier formulations.