Mechanical characterization of multi-layered lipid nanoparticles using high-resolution AFM force spectroscopy

Lipid nanoparticles (LNPs) have been widely used in drug delivery systems. Their physicochemical properties play a substantial role in the pharmaceutical functions and therapeutic efficacy of encapsulated drugs. Although, numerous previous studies have examined the optimal physicochemical properties for drug delivery, the role of LNP mechanical compliance has not yet been established, owing to limitations imposed by their small size, extreme softness, and complex structures. The aim of this study was to delineate the true topography and the map of elastic moduli of LNPs by analyzing atomic force microscope (AFM) force spectroscopic data based on the modified Hertz model considering the asymptotic approach. Results reveal a hard core-soft shell structure of LNPs. Additionally, the elastic moduli of the core of LNPs are modulated from 176 kPa to 599 kPa through the addition of crosslinked alginate. However, a consistent elastic modulus (∼128 kPa) of outer shells is maintained regardless of core composition. In addition, Transwell assay show that, compared to rigid LNPs, those with soft properties exhibit enhanced permeation. This finding, which delineates the true topography and elastic moduli of LNPs, suggest an alternative for resolving the long-standing issues in AFM force spectroscopic studies.