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ACS Nano. 2019 Jun 12. doi: 10.1021/acsnano.9b01181. [Epub ahead of print]

Chain-Length- and Saturation-Tuned Mechanics of Fluid Nanovesicles Direct Tumor Delivery.

Dai Z1,2, Yu M2,3, Yi X4, Wu Z4, Tian F5, Miao Y1,2, Song W2, He S2, Ahmad E2, Guo S2, Zhu C2, Zhang X2, Li Y1, Shi X3,5, Wang R1, Gan Y2,3.

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School of Pharmacy , Shanghai University of Traditional Chinese Medicine , Shanghai 201203 , China.
Shanghai Institute of Materia Medica , Chinese Academy of Sciences , Shanghai 201203 , China.
University of Chinese Academy of Sciences , Beijing 100049 , China.
Beijing Innovation Center for Engineering Science and Advanced Technology, and Department of Mechanics and Engineering Science, College of Engineering , Peking University , Beijing 100871 , China.
CAS Key Laboratory for Nanosystem and Hierarchy Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology , Chinese Academy of Sciences , Beijing 100190 , China.


Small unilamellar vesicles (SUVs), ubiquitous in organisms, play key and active roles in various biological processes. Although the physical properties of the constituent lipid molecules ( i.e., the acyl chain length and saturation) are known to affect the mechanical properties of SUVs and consequently regulate their biological behaviors and functions, the underlying mechanism remains elusive. Here, we combined theoretical modeling and experimental investigation to probe the mechanical behaviors of SUVs with different lipid compositions. The membrane bending rigidity of SUVs increased with increasing chain length and saturation, resulting in differences in the vesicle rigidity and deformable capacity. Furthermore, we tested the tumor delivery capacity of liposomes with low, intermediate, and high rigidity as typical models for SUVs. Interestingly, liposomes with intermediate rigidity exhibited betterĀ tumor extracellular matrix diffusion and multicellular spheroid (MCS) penetration and retention than that of their stiffer or softer counterparts, contributing to improved tumor suppression. Stiff SUVs had superior cellular internalization capacity but intermediate tumor delivery efficacy. Stimulated emission depletion microscopy directly showed that the optimal formulation was able to transform to a rod-like shape in MCSs, which stimulated fast transport in tumor tissues. In contrast, stiff liposomes hardly deformed, whereas soft liposomes changed their shape irregularly, which slowed their MCS penetration. Our findings introduce special perspectives from which to map the detailed mechanical properties of SUVs with different compositions, provide clues for understanding the biological functions of SUVs, and suggest that liposome mechanics may be a design parameter for enhancing drug delivery.


ECM penetration; SUVs; chain length and saturation; liposome; membrane mechanics; tumor delivery; vesicle rigidity


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