Nanomimics of Host Cell Membranes Block Invasion and Expose Invasive Malaria Parasites

Abstract

The fight against most infectious diseases, including malaria, is often hampered by the emergence of drug resistance and lack or limited efficacies of vaccines. Therefore, new drugs, vaccines, or other strategies to control these diseases are needed. Here, we present an innovative nanotechnological strategy in which the nanostructure itself represents the active substance with no necessity to release compounds to attain therapeutic effect and which might act in a drug- and vaccine-like dual function. Invasion of Plasmodium falciparum parasites into red blood cells was selected as a biological model for the initial validation of this approach. Stable nanomimics-polymersomes presenting receptors required for parasite attachment to host cells-were designed to efficiently interrupt the life cycle of the parasite by inhibiting invasion. A simple way to build nanomimics without postformation modifications was established. First, a block copolymer of the receptor with a hydrophobic polymer was synthesized and then mixed with a polymersome-forming block copolymer. The resulting nanomimics bound parasite-derived ligands involved in the initial attachment to host cells and they efficiently blocked reinvasion of malaria parasites after their egress from host cells in vitro. They exhibited efficacies of more than 2 orders of magnitude higher than the soluble form of the receptor, which can be explained by multivalent interactions of several receptors on one nanomimic with multiple ligands on the infective parasite. In the future, our strategy might offer interesting treatment options for severe malaria or a way to modulate the immune response.

Giant Host Red Blood Cell Membrane Mimicking Polymersomes Bind Parasite Proteins and Malaria Parasites

“…[4,5] Furthermore, we measured that several heparin chains on a single nanomimic bound parasite ligands PfMSP1 42 -OG488 with a high affinity (K d of 12.1 ± 1.6 nM) using fluorescence crosscorrelation spectroscopy (FCCS) of green labelled ligand and red labelled nanomimics. [5] This multiple binding with high affinity is the basis for a strong multivalent interaction of nanomimic and merozoite, explaining the potent invasion inhibition by nanomimics.…”

“…If successful in vivo, this artificial inhibition of merozoite invasion could lead to an immune boost against extracellular merozoites. [4] Here, we demonstrate that RBC membrane mimics formed at a larger size, but with similar hollow sphere architecture (heparin GUVs), can also bind the parasite protein PfMSP1 42 and the whole Plasmodium parasite (merozoite form) in a similar fashion as their nano-sized counterparts, the nanomimics. [4,5] This indicates that GUVs indeed represent a suitable model of small polymersomes, with the advantage of a size close to that of RBCs.…”

“…Usually, a large number of mainly unilamellar, univesicular polymersomes were formed, whereas only few giants with multivesicular structures were found. Interestingly, these artificial and flexible membranes possess a thickness of about 11 nm, [4] whilst all the membrane components can laterally diffuse within the membrane, [12,13] but still form stable vesicles with several tens of micrometers in diameter. We performed CLSM to study the interaction of fluorescently labelled Plasmodium ligand PfMSP1 42 -OG488 and heparin, the receptor-like molecule known to bind PfMSP1 42 , [9] on the surface filters.…”

“…[2,3] Our recently developed nanomimic strategy against infectious diseases is based on such polymer vesicles imitating a host cell membrane at the nanoscale (nanomimics), which was achieved by mixing two distinct block copolymers: vesicle-forming poly(2-methyl-2-oxazoline)-blockpoly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PMOXA-b-PDMSb-PMOXA), and PDMS-b-heparin. [4,5] Giant polymersomes (giant unilamellar vesicles, GUVs), several micrometers in diameter, are increasingly acknowledged as interesting model systems of very simplified cell mimics. [6] Malaria, a disease caused by Plasmodium spp.…”

Resisting resistance: is there a solution for malaria?

“…Alternatively, nanomimics that present specific host cell receptors on their surface bind to egressed daughter merozoites, preventing their ability to invade new erythrocytes and making them completely accessible to the immune system. This strategy might offer alternative treatment options for severe malaria or a new way to modulate the immune response [77]. Moreover, this strategy makes it nearly impossible for the parasite to evade these "pseudo" receptors on the nanomimic without compromising its regular route of entry into the erythrocyte.…”