Virus-mimetic Nanoparticles

病毒和生物医学纳米颗粒都试图将分子传递到特定的靶细胞，以引发独特的生物效应。然而，更仔细的比较表明，纳米粒子的效率远远低于它们的“天然”对应物。与纳米颗粒相比，病毒具有通过采取一系列逻辑决策来区分细胞的能力，并且对靶细胞的亲和力高出10至100倍。潜在的机制依赖于它们冠中高度不同的、经常相互作用的分子接触点，它们通过这些接触点扫描潜在的靶细胞。因此，与纳米颗粒的差异是戏剧性的。虽然像HIV-1这样的病毒只需要8-10个纳米粒子就可以识别它们的靶细胞，但今天典型的纳米粒子配备了1000 - 10000个纳米粒子，但仍然无法区分细胞。该项目的目标将是为纳米颗粒提供决定性的设计标准，以缩小这一巨大的功效差距。为此，纳米颗粒将由已建立的和良好表征的嵌段共聚物制成，以获得对颗粒表面结构动力学的完全控制。这将允许模拟与细胞相互作用的病毒策略，以研究它们对细胞类型选择性、亲合力、细胞摄取和细胞内命运的影响。为了赋予颗粒以病毒区分细胞的能力，我们将建立一些迄今未知的方法。 我们将设计决策纳米粒子，获得其增强的能力，以区分细胞之间的相互作用，完全从酶在细胞膜。迄今为止，这一未模拟的病毒原理将允许高靶细胞特异性，并使治疗性纳米材料的预期生物效应与可能由经典配体受体相互作用引起的不期望的“副作用”脱钩。此外，我们将开发一种技术，允许测量粒子同时与细胞结合的配体数量。此外，我们将研究细胞膜内陷，特别是网格蛋白包被的小坑对颗粒亲合力的影响。毕竟，我们将对病毒模拟颗粒的优化原型进行测试，并研究它们是否允许模拟病毒与细胞的相互作用。如果成功，这可能为新的抗病毒治疗策略打开大门。总的来说，仿生方法有助于更好地理解纳米颗粒如何与细胞相互作用，并在未来设计更有效的纳米药物。

Viruses and biomedical nanoparticles alike try to deliver molecules to defined target cells to elicit a distinct biological effect. However, a closer comparison reveals that nanoparticles are by far less efficient than their ‘natural’ counterparts. Viruses have in contrast to nanoparticles the ability to distinguish between cells by taking a series of logic decisions and are outfitted with 10- to 100-fold higher avidities for their target cells. The underlying mechanism rests on highly distinct, frequently interactive molecular contact points in their corona by which they scan prospective target cells. The differences to nanoparticles are thereby dramatic. While viruses like HIV-1 need only 8-10 of them to identify their target cells, todays’ typical nanoparticles are outfitted with 1.000-10.000 but are still unable to distinguish between cells. Goal of this project will be to outfit nanoparticles with the decisive design criteria to close this huge efficacy gap. To this end nanoparticles will be made of established and well-characterized block copolymers to obtain full control over the particles’ surface structure dynamics. This will allow to mimic viral strategies of interacting with cells to investigate their effect on cell type selectivity, avidity, cell uptake and intracellular fate. To endow particles with the ability of viruses to distinguish between cells, we will establish a number of to date unknown methods. We will design decision-making nanoparticles that acquire their enhanced ability to distinguish between cells exclusively from interactions with enzymes in the cell membrane. This to date not mimicked viral principle will allow for high target cell specificity and for decoupling intended biological effects of a therapeutic nanomaterial from undesired ‘side effects’ that may result from classical ligand receptor interactions. Furthermore, we will develop a technique that allows to measure the number of ligands by which particles simultaneously bind to cells. Moreover, we will investigate the impact of cell membrane invaginations especially of clathrin coated pits on particle avidity. After all we will put optimized prototypes of virus-mimetic particles to the test and investigate if they allow to mimic viral interactions with cells. If successful, this could open the door to new antiviral therapeutic strategies. Overall, the biomimetic approach can contribute to a better understanding of how nanoparticles interact with cells and to design more efficient nanomedicines in the future.