Inhibition of SARS-CoV-2 replication in the lung with siRNA/VIPER polyplexes

Baldassi, Domizia; Ambike, Shubhankar; Feuerherd, Martin; Cheng, Cho-Chin; Peeler, David J.; Feldmann, Daniel P.; Porras-Gonzalez, Diana; Wei, Xin; Keller, Lea-Adriana; Kneidinger, Nikolaus; Stoleriu, Mircea Gabriel; Popp, Andreas; Burgstaller, Gerald; Pun, Suzie H.; Michler, Thomas; Merkel, Olivia M.

doi:10.1016/j.jconrel.2022.03.051

Cited by 25 publications

(13 citation statements)

References 55 publications

(72 reference statements)

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“…developed a virus-inspired polymer for endosomal release (VIPER) [ 182 ], which was applied for efficient pulmonary delivery of siRNA both in vitro and in vivo [ 183 ]. VIPER/siRNA polyplexes also showed antiviral effect by promoting suppression of viral replication of SARS-CoV-2 ex vivo in human lung tissues and in mouse models [ 184 ].…”

Section: Lung As Targetmentioning

confidence: 99%

“…For example, Pun et al developed a virus-inspired polymer for endosomal release (VIPER) [182], which was applied for efficient pulmonary delivery of siRNA both in vitro and in vivo [183]. VIPER/siRNA polyplexes also showed antiviral effect by promoting suppression of viral replication of SARS-CoV-2 ex vivo in human lung tissues and in mouse models [184]. Furthermore, small chemical compounds, which have already been used effectively as drugs for asthma treatment were used as targeting ligands coupled to synthetic nucleic acid carriers for targeted nucleic acid delivery to the lung.…”

Section: Lung As Targetmentioning

confidence: 99%

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Directing the Way—Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Steffens¹,

Wagner

2022

Pharm Res

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Nucleic acid therapeutics have shown great potential for the treatment of numerous diseases, such as genetic disorders, cancer and infections. Moreover, they have been successfully used as vaccines during the COVID-19 pandemic. In order to unfold full therapeutical potential, these nano agents have to overcome several barriers. Therefore, directed transport to specific tissues and cell types remains a central challenge to receive carrier systems with enhanced efficiency and desired biodistribution profiles. Active targeting strategies include receptor-targeting, mediating cellular uptake based on ligand-receptor interactions, and chemical targeting, enabling cell-specific delivery as a consequence of chemically and structurally modified carriers. With a focus on synthetic delivery systems including polyplexes, lipid-based systems such as lipoplexes and lipid nanoparticles, and direct conjugates optimized for various types of nucleic acids (DNA, mRNA, siRNA, miRNA, oligonucleotides), we highlight recent achievements, exemplified by several nucleic acid drugs on the market, and discuss challenges for targeted delivery to different organs such as brain, eye, liver, lung, spleen and muscle in vivo.

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Section: Lung As Targetmentioning

confidence: 99%

Section: Lung As Targetmentioning

confidence: 99%

Directing the Way—Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Steffens¹,

Wagner

2022

Pharm Res

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“…This method effectively suppressed COVID-19 infection prevalence. This NP demonstrated the potential of local siRNA transfer as an effective antiviral therapy in the lung by carrying siRNA to lung epithelial cells and interfering with substantial downregulation of viral replication both in vitro and ex vivo without producing toxic or immunogenic side effects [ 71 ].…”

Section: Nanoparticles As a Preventive Strategy In Covid-19mentioning

confidence: 99%

Therapeutic and diagnostic applications of nanoparticles in the management of COVID-19: a comprehensive overview

Gholizadeh

Yasamineh

Amini

et al. 2022

Virol J

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In December 2019, Coronavirus Disease 2019 (COVID-19) was reported in Wuhan, China. Comprehensive strategies for quick identification, prevention, control, and remedy of COVID-19 have been implemented until today. Advances in various nanoparticle-based technologies, including organic and inorganic nanoparticles, have created new perspectives in this field. These materials were extensively used to control COVID-19 because of their specific attribution to preparing antiviral face masks, various safety sensors, etc. In this review, the most current nanoparticle-based technologies, applications, and achievements against the coronavirus were summarized and highlighted. This paper also offers nanoparticle preventive, diagnostic, and treatment options to combat this pandemic. Graphical Abstract

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“…Due to its large surface area, low enzymatic activity and ease of access, the development of formulations for direct administration to the lung appears as a promising strategy [6]. Furthermore, the development of an siRNA therapy for direct administration to the airways could be beneficial for treating several pathological conditions affecting the lung for which no curing treatment is available yet, such as cystic fibrosis, asthma, acute lung injury, lung cancer but also viral infections as in the case of the recent SARS-CoV-2 outbreak [7][8][9][10][11]. Although two siRNA formulations reached clinical trials for intranasal administration, no formulation for Domizia Baldassi and Thi My Hanh Ngo contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Lung Surfactant Coating of siRNA Polyplexes for Pulmonary Delivery

2022

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Purpose The aim of this study was to understand how coating with a pulmonary surfactant, namely Alveofact, affects the physicochemical parameters as well as in vitro behavior of polyethylenimine (PEI) polyplexes for pulmonary siRNA delivery. Methods Alveofact-coated polyplexes were prepared at different Alveofact:PEI coating ratios and analyzed in terms of size, PDI and zeta potential as well as morphology by transmission electron microscopy. The biological behavior was evaluated in a lung epithelial cell line regarding cell viability, cellular uptake via flow cytometry and gene downregulation by qRT-PCR. Furthermore, a 3D ALI culture model was established to test the mucus diffusion and cellular uptake by confocal microscopy as well as gene silencing activity by qRT-PCR. Results After optimizing the coating process by testing different Alveofact:PEI coating ratios, a formulation with suitable parameters for lung delivery was obtained. In lung epithelial cells, Alveofact-coated polyplexes were well tolerated and internalized. Furthermore, the coating improved the siRNA-mediated gene silencing efficiency. Alveofact-coated polyplexes were then tested on a 3D air-liquid interface (ALI) culture model that, by expressing tight junctions and secreting mucus, resembles important traits of the lung epithelium. Here, we identified the optimal Alveofact:PEI coating ratio to achieve diffusion through the mucus layer while retaining gene silencing activity. Interestingly, the latter underlined the importance of establishing appropriate in vitro models to achieve more consistent results that better predict the in vivo activity. Conclusion The addition of a coating with pulmonary surfactant to polymeric cationic polyplexes represents a valuable formulation strategy to improve local delivery of siRNA to the lungs. Graphical Abstract

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Inhibition of SARS-CoV-2 replication in the lung with siRNA/VIPER polyplexes

Cited by 25 publications

References 55 publications

Directing the Way—Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Directing the Way—Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Therapeutic and diagnostic applications of nanoparticles in the management of COVID-19: a comprehensive overview

Optimization of Lung Surfactant Coating of siRNA Polyplexes for Pulmonary Delivery

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