Membrane mechanics as critical quality attributes in liposomal drug delivery: linking bilayer structure, mechanics,...

Mechanical properties of liposomes, particularly bending rigidity (k_c), membrane area compressibility modulus (k_a), and effective Young's modulus (E), are increasingly recognized as potentially important factors influencing clinical translation and regulatory assessment. This review establishes liposome mechanics as an underexplored determinant in predictive performance, moving beyond conventional descriptors such as size and surface charge. We provide an in-depth, systematic analysis of how bilayer mechanics governs key biological processes, including circulatory stability, deformability, trans-barrier transport, and cellular uptake. Special emphasis is placed on elastic liposomes, in which a reduction in k_c (often to <10 kBT) and modulation of k_a enable extreme deformability, facilitating pore-squeezing and enhanced tissue penetration. We integrate fundamental frameworks such as Helfrich elasticity with experimental and computational approaches (atomic force microscopy, micropipette aspiration, scattering, and molecular dynamics) to establish quantitative structure-mechanics-function relationships. The review further examines how lipid composition, sterols, and edge activators tune mechanical constants and how these parameters translate into drug-delivery performance. Emerging concepts such as mechanomorphic liposomes and mechanically triggered drug release are also critically discussed. Importantly, we discuss the potential for parameters such as k_c and k_a to be considered as future CQAs, pending further standardization and validation of measurement methodologies. This review, therefore, provides a roadmap for engineering mechanics-driven liposomal systems.