Analytical characterization of liposomes and other lipid nanoparticles for drug delivery

Lipid nanoparticles, especially liposomes and lipid/nucleic acid complexed nanoparticles have shown great success in the pharmaceutical industry. Their success is attributed to stable drug loading, extended pharmacokinetics, reduced off-target side effects, and enhanced delivery efficiency to disease targets with formidable blood-brain or plasma membrane barriers. Therefore, they offer promising formulation options for drugs limited by low therapeutic indexes in traditional dosage forms and current "undruggable" targets. Recent development of siRNA, antisense oligonucleotide, or the CRISPR complex-loaded lipid nanoparticles and liposomal vaccines also shed light on their potential in enabling versatile formulation platforms for new pharmaceutical modalities. Analytical characterization of these nanoparticles is critical to drug design, formulation development, understanding in vivo performance, as well as quality control. The multi-lipid excipients, unique core-bilayer structure, and nanoscale size all underscore their complicated critical quality attributes, including lipid species, drug encapsulation efficiency, nanoparticle characteristics, product stability, and drug release. To address these challenges and facilitate future applications of lipid nanoparticles in drug development, we summarize available analytical approaches for physicochemical characterizations of lipid nanoparticle-based pharmaceutical modalities. Furthermore, we compare advantages and challenges of different techniques, and highlight the promise of new strategies for automated high-throughput screening and future development.