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.
