The physico-mechanical properties of nanoscale lipid vesicles (e.g., natural nano-vesicles and artificial nano-liposomes) dictate their interaction with biological systems. Understanding the interplay between vesicle size and stiffness is critical to both the understanding of the biological functions of natural nano-vesicles and the optimization of nano-vesicle-based diagnostics and therapeutics. It has been predicted that, when vesicle size is comparable to its membrane thickness, the effective bending stiffness of the vesicle increases dramatically due to both the entropic effect as a result of reduced thermal undulation and the nonlinear curvature elasticity effect. Through systematic molecular dynamics simulations, we show that the vesicle membrane thins and softens with the decrease in vesicle size, which effectively counteracts the stiffening effects as already mentioned. Our simulations indicate that the softening of nano-vesicles results from a change in the bilayer’s interior structure – a decrease in lipid packing order – as the membrane curvature increases. Our work thus leads to a more complete physical framework to understand the physico-mechanical properties of nanoscale lipid vesicles, paving the way to further advances in the biophysics of nano-vesicles and their biomedical applications.

纳米级脂质囊泡（例如，天然纳米囊泡和人工纳米脂质体）的物理机械特性决定了它们与生物系统的相互作用。了解囊泡大小和刚度之间的相互作用对于理解天然纳米囊泡的生物学功能和优化基于纳米囊泡的诊断和治疗方法都至关重要。据预测，当囊泡大小与其膜厚度相当时，由于热波动减少导致的熵效应和非线性曲率弹性效应，囊泡的有效弯曲刚度显着增加。通过系统的分子动力学模拟，我们表明囊泡膜随着囊泡大小的减小而变薄和软化，这有效地抵消了已经提到的硬化效应。我们的模拟表明，随着膜曲率的增加，纳米囊泡的软化是由于双层内部结构的变化——脂质堆积顺序的降低——引起的。因此，我们的工作导致了一个更完整的物理框架来理解纳米级脂质囊泡的物理机械特性，为纳米囊泡的生物物理学及其生物医学应用的进一步发展铺平了道路。