Safe and effective inhalable nanocatchers that contain human angiotensin-converting enzyme II (hACE2) have been recently developed by a group of researchers from China, providing a plethora of potential benefits in comparison to existing treatments against the coronavirus disease 2019 (COVID-19). The exact approach is delineated in-depth in a paper published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
Image Credit: National Academy of Sciences
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike glycoprotein on the surface to bind with the hACE2 for cell entry and subsequent infection. Consequently, the mutations of this glycoprotein can optimize its binding properties and, in turn, make the virus more transmissible and pathogenic.
Some studies have already investigated how cellular nanovesicles that harbor hACE2 can compete with host cells for SARS-CoV-2 binding, safeguarding them from infection. For example, one of them observed the activity of cellular nanosponges made from human macrophages or human lung epithelial type II cells.
Another study described decoy nanoparticles that can protect against COVID-19 by simultaneously adsorbing viruses and inflammatory cytokines, the latter being signaling molecules that are secreted from our immune cells (most notably helper T cells and macrophages).
In this new paper, a research group led by Dr. Han Zhang from the Institute of Functional Nano and Soft Materials at the Soochow University in Suzhou (China) designed ingenious hACE2-containing inhalable nanocatchers that act as competitors with host cells for viral binding.
Genetic engineering in full throttle
The approach of these researchers was to genetically engineer human embryonic kidney 293T cells with high expression (i.e. high density) of hACE2 in the form of neutralizing nanocatchers. Their spherical morphology was demonstrated with the use of electron microscopy and dynamic light scattering, and an average diameter was found to be around 200 nanometers.
Encouraged by such successful preparation of hACE2-containing nanocatchers, the researchers next aimed to assess their neutralization activity of SARS-CoV-2 by binding with its spike glycoprotein using. A vesicular stomatitis virus (VSV)–based pseudotyped SARS-CoV-2 was used as a model for this purpose (both wild-type and the D614G variant).
Finally, to prevent lung infection with SARS-CoV-2, they have developed an inhalable formulation by mixing hACE2-containing nanocatchers with mucoadhesive excipient hyaluronic acid, with the end goal to prolong the retention of nanocatchers in the lung after inhalation. This was also tested in a hACE2-expressing mouse model.
Successfully targeting viral binding
In conclusion, the hACE2-containing nanocatchers showed excellent neutralization propensity against pseudoviruses of both the wild-type SARS-CoV-2 and the D614G variant, which means they could act as potent competitors with host cells for viral binding - regardless of mutations.
Furthermore, mucoadhesive excipient hyaluronic acid was able to substantially improve the retention of nanocatchers in the lung, emphasizing a rather vigorous SARS-CoV-2 pseudovirus inhibition ability in the mouse model (primarily by using replication-defective adenovirus encoding for hACE2).
Even more importantly, nanocatchers were successfully developed in the lyophilized formulation with the assistance of cryoprotectant sucrose, increasing, in turn, the feasibility of their clinical usage (which includes transport issues and long-term storage).
A promising non-invasive strategy
The inhalation of drug-loaded nanoparticles represents a promising non-invasive strategy for the treatment of pulmonary diseases due to ease of administration, low systemic adverse effects, and favorable patient compliance. Furthermore, this study has shown that large-scale and timely production of hACE2-containing nanocatchers with the use of an engineered cell line is actually a feasible approach.
Our proposed strategy may have the potential to be implemented in the battle against COVID-19, especially in this urgent period with the frequent emergence of mutated viral strains”
Importantly, inhalable nanocatchers in the lyophilized formulation would enable long-term storage and, consequently, facilitate their future clinical usage. Hence, this work shed some light on one viable alternative approach to inhibit the infection with SARS-CoV-2 – even when faced with a rising number of mutations and variants of concern.
- Rao, L. et al. (2020). Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines. PNAS. https://doi.org/10.1073/pnas.2014352117.
- Zhang, Q. et al. (2020). Cellular Nanosponges Inhibit SARS-CoV-2 Infectivity. Nano Letters. https://doi.org/10.1021/acs.nanolett.0c02278.