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Review
. 2022 Feb 22;23(5):2408.
doi: 10.3390/ijms23052408.

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Yuan Zhang  1 , Juhura G Almazi  2   3 , Hui Xin Ong  2   3 , Matt D Johansen  4 , Scott Ledger  1 , Daniela Traini  2   3 , Philip M Hansbro  4 , Anthony D Kelleher  1 , Chantelle L Ahlenstiel  1
Affiliations
Review

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Yuan Zhang et al. Int J Mol Sci. .

Abstract

Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.

Keywords: COVID-19; glycogen nanoparticles; inhalation; lipid nanoparticles; nanomedicine; nanoparticle-capsulated drug delivery; polymer nanoparticles; siRNA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of siRNA therapy. PTGS primarily occurs in the cytoplasm. The guide strand binds to Ago-2 of RISC, while the non-guide strand is cleaved and ejected by the Ago-2; Ago-2 carries the guide strand to target mRNA, causing gene expression silencing. TGS has taken place in the nucleus. siRNA binds to Ago-1 on RITS, which contributes to the production of heterochromatin and induces the epigenetic silencing of the gene. PTGS, post-transcriptional gene silencing pathway; TGS, transcriptional gene silencing; Ago-1, Argonaute-1 protein; Ago-2, Argonaute-2 protein; RISC, RNA-induced silencing complex; RITS, RNA-induced transcriptional silencing complex. Created with BioRender.com.
Figure 2
Figure 2
Comparison of different nanocarriers. Advanced nanocarriers can be divided into organic NPs (lipid NPs, polymers NPs, and glycogen NPs) and inorganic NPs (gold NPs and magnetic NPs) according to their size, structures, and characteristics. NPs, nanoparticles; NLCs, nanostructured lipid carriers; LNPs, lipid nanoparticles. Created with BioRender.com.
Figure 3
Figure 3
Structures of liposomes and cationic LNPs. (A) Liposomes: small-molecule artificial vesicles with a hydrophobic phospholipid double layer outside and a hydrophilic core inside. (B) Cationic LNPs: spherical particles composed of ionizable cationic lipids, cholesterol, phospholipids, and PEGylated lipids. LNPs, lipid nanoparticles; PEG, polyethylene glycol. Created with BioRender.com.
Figure 4
Figure 4
Intravenous delivery vs. lung delivery of NP-siRNAs. Intravenous delivery can deliver therapeutic siRNAs directly to the liver via the circulatory system. Lung delivery can deliver siRNAs into the respiratory tract through the mouth or nose, and the deposition distance depends mainly on the size and density of the particles. Aerosols with an aerodynamic diameter >10 µm will deposit in the nasal cavity and pharynx through impact, and particles with a diameter of ˂10 nm with high diffusion velocity are more likely to be deposited in the upper respiratory tract [231,232]. Particles between ~1 and 10 µm will be deposited in the bronchi and bronchioles through sedimentation; particles with diameters ranging between 10 and 500 nm will deposit in the lower bronchioles and alveoli by diffusion. Created with BioRender.com.
Figure 5
Figure 5
Examples of different inhalation devices. Inhalation devices are divided into nebulizer, inhaler (including pMDIs, DPIs, and SMIs), and nasal spray. pMDIs, pressurized metered dose inhalers; DPIs, dry powder inhalers; SMIs, soft mist inhalers. Created with BioRender.com.
Figure 6
Figure 6
Types of impactors. (A) Andersen cascade impactor; (B) multi-stage liquid impinger; (C) twin-stage impinger; (D) next-generation impactor; (E) fast-screening impactor. Adapted from images from www.copleyscientific.com.
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