Lipid nanoparticles with ionizable lipids: Statistical aspects

Journal article, 2022

Lipid nanoparticles (LNPs) with size ∼100 nm are now used for fabrication of a new generation of drugs and antiviral vaccines. To optimize their function or, more specifically, interaction with cell membranes, their composition often includes ionizable lipids which are neutral or cationic (after association with H+). Physically, such LNPs represent an interesting example of mesoscopic nanosystems with complex and far from understood properties. Experimentally, they can be studied at cell-membrane mimics. Herein, I analyze theoretically three related aspects. (i) I describe how the extent of protonation of ionizable lipids located at the surface of LNPs depends on the H+ concentration by using the phenomenological Langmuir-Stern and Poisson-Boltzmann models with continuum distribution of charges and the dipole model with discrete charges. In these frameworks, the H+ adsorption isotherms are predicted to be close to Langmuirian provided the fraction of ionizable lipids is smaller than 0.5. (ii) I scrutinize the interaction between charged LNPs and their interaction with a supported lipid bilayer (SLB) by using the phenomenological theory and lattice-gas model. The long-term association or attachment is predicted provided the charges are opposite. The models make it possible to estimate the size of the contact region (provided a LNP is not deformed) and the number of lipid-lipid bonds in this region. (iii) I briefly discuss denaturation of a LNP during interaction with the SLB and argue that it may occur via a few stepwise transitions.