Non-Lamellar Lyotropic Liquid Crystalline Lipid Nanoparticles for the Next Generation of Nanomedicine

Nonlamellar lyotropic liquid crystalline (LLC) lipid nanomaterials have emerged as a promising class of advanced materials for the next generation of nanomedicine, comprising mainly of amphiphilic lipids and functional additives self-assembling into two- and three-dimensional, inverse hexagonal, and cubic nanostructures. In particular, the lyotropic liquid crystalline lipid nanoparticles (LCNPs) have received great interest as nanocarriers for a variety of hydrophobic and hydrophilic small molecule drugs, peptides, proteins, siRNAs, DNAs, and imaging agents. Within this space, there has been a tremendous amount of effort over the last two decades elucidating the self-assembly behavior and structure–function relationship of natural and synthetic lipid-based drug delivery vehicles in vitro, yet successful clinical translation remains sparse due to the lack of understanding of these materials in biological bodies. This review provides an overview of (1) the benefits and advantages of using LCNPs as drug delivery nanocarriers, (2) design principles for making LCNPs with desirable functionalities for drug delivery applications, (3) current understanding of the LLC material–biology interface illustrated by more than 50 in vivo, preclinical studies, and (4) current patenting and translation activities in a pharmaceutical context. Together with our perspectives and expert opinions, we anticipate that this review will guide future studies in developing LCNP-based drug delivery nanocarriers with the objective of translating them into a key player among nanoparticle platforms comprising the next generation of nanomedicine for disease therapy and diagnosis.