Article by Derek Ning & Roberta Lock
Combatting Infectious Diseases with Nanotechnology
Potent Virustatic Polymer–Lipid Nanomimics Block Viral Entry and Inhibit Malaria Parasites In Vivo, ACS Central Science, 2022
Adrian Najer et al., Molly Stevens Lab
The emergence of infectious diseases such as SARS-Cov2 and parasitic diseases like malaria continue to infect millions of people around the world, representing a significant need for easily deployable treatment strategies that can be applied against many different intracellular pathogens. Nanotechnology represents a promising but little explored direction in terms of inhibiting parasite and virus entry into host cells.This paper details the development of a nanomimic (a nano-scale synthetic material that mimics a specific part of a cell) that’s able to significantly prevent virus and parasite entry for three different diseases: herpes simplex virus type 2 (HSV-2), SARS-Cov2, and the malarial Plasmodium parasite. This proven modular nanomimic design shows great promise for the future in developing speedy and effective methods to fight viral diseases around the world.
What did these researchers do?
This study developed and tested modular synthetic polymer and polymer-lipid nanomimics that are able to inhibit the entry of different viruses and parasites. The general principle behind why this works is that many of these pathogens enter a cell in the same way, by interacting with specific proteins on the cell surface, so if the nanomimic mimics these proteins and enters the bloodstream, the pathogens are essentially tricked into binding to the nanomimic instead of the receptors on your cells, thus stopping their invasion.
The nanomimics were tested first for their safety, and were validated as being cytocompatible (e.g. they don’t harm the cells in your body). Then they were tested and modified for certain properties to remain in the blood circulation for as long as possible, because in order to inhibit pathogens, they need to remain stable in circulation for at least a few hours. Next the nanomimics were tested for their actual ability to prevent virus entry.
The nanomimics were found to be extremely effective virus entry inhibitors for both herpes simplex virus (HSV-2) and SARS-CoV-2 (at higher doses than HSV-2) with a better performance relative to other studied inhibitors such as heparin and multivalent gold nanoparticles. The potency can be attributed in part to the polymer chains which allows for flexibility and optimal binding when interacting with viral envelope proteins in contrast to more rigid structures in other types of nanoparticles (Figure 1). Finally, these nanomimics were tested on a second pathogen (malaria parasite (Plasmodium)) to see if it’s efficacy has the potential to be more broadly applied, and found that the nanomimics were also potent inhibitors of malaria parasite invasion of red blood cells.
Illustration of inhibited by host-mimicking nanoparticles inhibiting malaria parasites
Why is this important?
First, this paper demonstrated a major step forward in terms of developing copolymers that are safe and have prolonged blood circulation times. This is a huge advance as this was one of the main limitations of these copolymers in the past, because ability to stably remain in the body is a requirement for effectively combating pathogens. Moreover, this nanomimic design is flexible and modular, meaning it can be modified to work against multiple pathogens and has the potential for additional applications like controlled drug delivery, making it a very promising technology for a wide variety of future purposes.
How did the researchers do this?
To make the nanomimics, a block copolymer was synthesized, combining repetitive pathogen-binding units (PAA) with a degradable hydrophobic block (PDLLA). PAA is able to be easily chemically modified to adjust surface chemistry leading to the optimization of pathogen binding by mimicking some properties of the host cell membranes. The PAA is the modular part that can be modified depending on future applications. Then to extend the blood circulation time of the surface-active nanoparticles, this modified copolymer was further coassembled with lipids to formulate polymer-lipid nanomimics (PLNs).
What comes next?
Currently the authors have performed initial studies to test the in vivo efficacy of these materials in mice, showing about 75% inhibition. In terms of next steps, the authors plan to perform further studies to see whether these nanomimics are applicable in vivo. Specifically, future investigations will involve looking at timing of nanomimic administration and the accompanying downstream effects on the immune system. Another avenue involves the incorporation of immunomodulatory modules in nanomimics which can further tune the immune response and contribute to protection from subsequent limitations. Additional important points to consider would include concerns such as cost, mass producibility, and stability, especially for diseases such as malaria which are most prevalent in low-income countries. Finally, before becoming a method of disease treatment and prevention that can be found in the clinic, extensive clinical trials will need to be conducted to see the response of the immune system to these nanomimics.