Virus-mimetic Nanoparticles

病毒和生物医学纳米颗粒都试图将分子运送到确定的目标细胞，以产生不同的生物效应。然而，更仔细的比较发现，纳米颗粒的效率远远低于它们的“天然”同行。与纳米粒子相比，病毒具有通过做出一系列逻辑决定来区分细胞的能力，并且对目标细胞的敏感度要高出10到100倍。潜在的机制依赖于它们日冕中高度不同的、频繁交互的分子接触点，它们通过这些接触点扫描未来的目标细胞。因此，与纳米颗粒的区别是巨大的。虽然像HIV-1这样的病毒只需要8-10个细胞来识别它们的目标细胞，但今天典型的纳米粒子配备了1.000-10.000个细胞，但仍然无法区分细胞。该项目的目标将是为纳米颗粒配备决定性的设计标准，以缩小这一巨大的功效差距。为此，纳米粒子将由已建立的和表征良好的嵌段共聚物制成，以获得对粒子表面结构动力学的完全控制。这将允许模拟病毒与细胞相互作用的策略，以研究它们对细胞类型选择性、亲和力、细胞摄取和细胞内命运的影响。为了赋予粒子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颗粒，以获得增强的能力，专门通过与细胞膜中的酶相互作用来区分细胞。到目前为止，这一尚未被模仿的病毒原理将允许高度的靶细胞特异性，并将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希望看到的“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的数量。此外，我们还将研究细胞膜内陷，特别是笼状蛋白包被的凹坑对颗粒亲和力的影响。毕竟，我们将对模拟病毒颗粒的优化原型进行测试，并研究它们是否可以模拟病毒与细胞的相互作用。如果成功，这可能会为新的抗病毒治疗策略打开大门。总体而言，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.