设计输运到人体的纳米药物受到越来越多的关注。肺器官作为一个药物输运的主要途径，相较于其它方式包括口服和注射更有优势。这是由于肺部的高渗透性、大表面积物质交换特性以及肺部给药的非侵入性。然而药物通过肺部进入循环系统仍然有很多挑战，其中主要障碍来自于肺表面活性剂膜。肺表面活性剂是由85%的磷脂、5%的胆固醇和10%的蛋白质组成。它能够吸附在气液界面，并通过形成一个单层膜来包裹肺内液体，从而减少表面张力、维持正常的呼吸。当颗粒到达肺的深处时会不可避免地与肺表面活性剂单层膜作用。纳米颗粒能否穿过该障碍取决于颗粒表面的物理化学性质以及膜表面的生物物理性质。

输运纳米颗粒总是通过表面修饰来增强生物兼容性。在纳米颗粒表面包裹上聚合物能有效减少颗粒表面的蛋白质吸附。一直以来，设计被包裹的纳米颗粒聚焦在控制和改变修饰材料的性质上。大量生物化学实验都指出了包裹聚合物的重要性，而纳米颗粒进入肺表面活性剂单层膜的程度取决于聚合物的种类、聚合物的修饰方式以及纳米颗粒表面电荷等因素。

我们建立了能够描述真实天然肺表面活性剂单层膜结构和各组分分子行为的粗粒化分子动力学模型以及聚乙二醇(PEG)修饰的金纳米颗粒的粗粒化模型。采用粗粒化分子动力学模拟方法研究了PEG修饰的纳米颗粒与肺表面活性剂单层膜的交互作用。通过调控PEG修饰纳米颗粒穿过肺表面活性剂单层膜，我们定量给出了PEG修饰的条件对纳米颗粒穿膜效果的影响及纳米颗粒对肺表面活性剂单层膜结构和生物物理性质的改变问题，并指明了最佳的方案。研究发现，负电荷、低PEG密度、合适的PEG链长将有利于纳米颗粒的穿膜输运。

肺表面活性剂单层膜生物物理特性对纳米颗粒穿膜有重要影响。在肺表面活性剂单层膜的各种生物物理特性中，最重要的是膜表面张力。使用Martini粗粒化模拟，我们探索了不同单层膜表面张力下的肺表面活性剂与PEG修饰的纳米颗粒的交互作用。研究发现肺表面活性剂单层膜表面张力越大越有利于纳米颗粒穿过肺表面活性剂单层膜。此外，我们发现肺表面活性剂单层膜中的蛋白质成分有利于纳米颗粒穿膜，并且纳米颗粒在穿膜过程中通过拽出磷脂和蛋白质的方式消耗肺表面活性剂单层膜的组分。

这些研究深化了表面修饰对纳米颗粒与肺表面活性剂单层膜交互作用的理解，对指导设计更具优势的纳米药物提供了重要信息。

Design of nanoparticles (NPs) for drug delivery to human body receives the increasing concerns. As a major means of drug delivery, lung organs have advantages over other methods including oral administration and injection. This is due to the high permeability of the lungs, the properties of substance exchange of large surface area, and the non-invasive nature of pulmonary administration. However, there are still many challenges for drugs to enter the circulatory system through the lungs, among which the main obstacle is the pulmonary surfactant (PS) membrane. The PS is composed of 85% phospholipids, 5% cholesterol and 10% protein. It can be adsorbed at the gas-liquid interface and encapsulates the fluid in the lungs as a monolayer, thereby reducing surface tension and maintaining normal breathing. When particles reach deep into the lung, they inevitably interact with the PS monolayer. Whether NPs can pass through the barrier depends on the physicochemical properties of the particle surface and the biophysical properties of the membrane surface.

NPs for drug delivery are always surface-modified to increase their bio-compatibility or functionality by regulating their surface properties. Grafting with polymers is efficient to eliminate the adsorption of proteins for NPs. Designing encapsulated NPs has been focusing on controlling and changing the properties of modified materials. A number of biochemical experiments have pointed out the importance of grafting the polymer, and the degree of NPs entering the PS monolayer depends on the type of polymer, the modification mode of polymer, surface charge of NPs and other factors

A coarse-grained molecular dynamics model and a gold nanoparticle coarse-grained model modified with polyethylene glycol (PEG) were established to describe the structure and molecular behavior of the real and natural PS monolayer. The interaction between the PEGylated nanoparticle and PS monolayer is studied by coarse-grained molecular dynamic simulations. The effect of PEG modification on the trans-membrane effect of NPs and the change of the structure and biophysical properties of the NPs on the PS monolayer were quantitatively studied. The results indicate that PEG chains with negative charge, low PEG density, and appropriate PEG chain length are more favorable for membrane penetration.

The biophysical properties of PS monolayer have important influence on the trans-membrane of NPs. The surface tension is the most important biophysical property of the PS monolayer. Using Martini coarse-grained simulations,

we explore the interaction between PS monolayer and PEGylated nanoparticle under different monolayer surface tension. It is found that the higher the surface tension of PS monolayer, the better the NPs can pass through the PS monolayer. In addition, we find that the protein components in the PS monolayer are favorable for the trans-membrane penetration of NPs, and the components of PS monolayer are consumed by the way of pulling out phospholipids and proteins during the trans-membrane penetration of NPs.

These studies have deepened the understanding of the interaction between NPs and the PS monolayer by surface modification and provided important information for guiding the design of more advantageous nano-drugs.