Mechanical insights into regulation of bio-nano interactions for lipid-based nanocarriers.

Lipid nanocarriers (LNCs), including liposomes, lipid nanoparticles (LNPs), and extracellular vesicles (EVs), are promising platforms for targeted drug delivery. However, their clinical translation is hindered by multi-level heterogeneity and complex behaviors at the bio-nano interface. Interest in mechanotargeted delivery strategies has grown rapidly, as the mechanical properties of LNCs are increasingly recognized as critical determinants of their in vivo behavior. Establishing a comprehensive database of mechanical properties to decipher the underlying regulatory mechanisms is a prerequisite for the active modulation of LNCs' mechanics and the rational design of delivery vehicles. Although studies on LNC mechanics are increasing, several challenges remain, including mechanical heterogeneity, unbalanced research across different carriers, low-throughput mechanical characterization and limited comparability among results from different laboratories. This review systematically summarizes the intrinsic mechanical parameters of the three types of LNCs, outlines the structural determinants of these properties, highlights their roles as key modulators at the bio-nano interface, and discusses advanced engineering strategies for mechanical modulation. The goal of this review is to facilitate mechanics-informed design of next-generation nanomedicines for precision therapy.