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Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19

Fang et al., Journal of Nanobiotechnology, doi:10.1186/s12951-024-02435-2

Apr 2024

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Quercetin for COVID-19

24th treatment shown to reduce risk in July 2021, now with p = 0.0031 from 11 studies.

Lower risk for ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19early.org

In Vitro study showing that nanoparticles coated with both ACE2-containing cell membranes and quercetin (CM-NP-Q) inhibit SARS-CoV-2 infection in human lung cells. Authors developed nanoparticles incorporated with quercetin (NP-Q), ACE2-containing cell membranes (CM-NP), or both (CM-NP-Q). CM-NP-Q showed the strongest antiviral activity by neutralizing extracellular pseudo-SARS-CoV-2 virus in ACE2-expressing H1975, 293T, and BEAS-2B cells, and inhibiting infection of H1299 lung cancer cells by both pseudo-SARS-CoV-2 and SARS-CoV-2/NTU13 virus. NP-Q and free quercetin also inhibited viral infection, but CM-NP-Q was most effective. The enhanced activity of CM-NP-Q is attributed to its ability to both neutralize extracellular virus through its ACE2-containing membrane and inhibit viral entry through quercetin's suppression of the AXL receptor. CM-NP-Q showed no significant cytotoxicity or in vivo toxicity in mice. The results suggest CM-NP-Q has potential as an inhaled therapy to prevent SARS-CoV-2 infection.

Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.

2 studies investigate novel formulations of quercetin for improved efficacy1,2

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1. Vaiss et al., Curcumin and quercetin co-encapsulated in nanoemulsions for nasal administration: a promising therapeutic and prophylactic treatment for viral respiratory infections, European Journal of Pharmaceutical Sciences, doi:10.1016/j.ejps.2024.106766.sciencedirect.com, doi.org.

2. Fang et al., Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19, Journal of Nanobiotechnology, doi:10.1186/s12951-024-02435-2.biomedcentral.com, doi.org.

Fang et al., 12 Apr 2024, peer-reviewed, 11 authors. Contact: pcyang@ntu.edu.tw, cychen@mail.cgust.edu.tw.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Quercetin All

Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19

Jia-You Fang, Kuo-Yen Huang, Tong-Hong Wang, Zih-Chan Lin, Chin-Chuan Chen, Sui-Yuan Chang, En-Li Chen, Tai-Ling Chao, Shuenn-Chen Yang, Pan-Chyr Yang, Chi-Yuan Chen

Journal of Nanobiotechnology, doi:10.1186/s12951-024-02435-2

Introduction Angiotensin-converting enzyme 2 (ACE2) and AXL tyrosine kinase receptor are known to be involved in the SARS-CoV-2 entry of the host cell. Therefore, targeting ACE2 and AXL should be an effective strategy to inhibit virus entry into cells. However, developing agents that can simultaneously target ACE2 and AXL remains a formidable task. The natural compound quercetin has been shown to inhibit AXL expression. Materials and methods In this study, we employed PLGA nanoparticles to prepare nanoparticles encapsulated with quercetin, coated with ACE2-containing cell membranes, or encapsulated with quercetin and then coated with ACE-2-containing cell membranes. These nanoparticles were tested for their abilities to neutralize or inhibit viral infection. Results Our data showed that nanoparticles encapsulated with quercetin and then coated with ACE2-containing cell membrane inhibited the expression of AXL without causing cytotoxic activity. Nanoparticles incorporated with both quercetin and ACE2-containing cell membrane were found to be able to neutralize pseudo virus infection and were more effective than free quercetin and nanoparticles encapsulated with quercetin at inhibition of pseudo virus and SARS-CoV-2 infection. Conclusions We have shown that the biomimetic nanoparticles incorporated with both ACE-2 membrane and quercetin showed the most antiviral activity and may be further explored for clinical application.

Data availability All data generated for this study are included in the article. Declarations Ethics approval and consent to participate The study involving SARS-CoV-2 was approved by the National Taiwan University Hospital Research Ethics Committee (202002002RIND). All of the mouse experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Chang Gung University (IACUC approval no.: CGU110-015) and Chang Gung Memorial Hospital (IACUC approval no.: 2020121704). Consent for publication Not applicable. Competing interests The authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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J Nanobiotechnol. 2018;16:35.', 'journal-title': 'J Nanobiotechnol'}, { 'key': '2435_CR46', 'doi-asserted-by': 'crossref', 'first-page': '40', 'DOI': '10.1038/s41389-020-0225-0', 'volume': '9', 'author': 'TH Wang', 'year': '2020', 'unstructured': 'Wang TH, Wu CC, Huang KY, Chuang WY, Hsueh C, Li HJ, Chen CY. Profiling ' 'of subcellular EGFR interactome reveals hnRNP A3 modulates nuclear EGFR ' 'localization. Oncogenesis. 2020;9:40.', 'journal-title': 'Oncogenesis'}, { 'key': '2435_CR47', 'doi-asserted-by': 'crossref', 'unstructured': 'Leu YL, Wang TH, Wu CC, Huang KY, Jiang YW, Hsu YC, Chen CY. ' 'Hydroxygenkwanin suppresses Non-small Cell Lung Cancer Progression by ' 'enhancing EGFR Degradation. Molecules 2020, 25.', 'DOI': '10.3390/molecules25040941'}, { 'key': '2435_CR48', 'doi-asserted-by': 'crossref', 'first-page': '4009', 'DOI': '10.1158/0008-5472.CAN-12-4066', 'volume': '73', 'author': 'CY Chen', 'year': '2013', 'unstructured': 'Chen CY, Jan CI, Lo JF, Yang SC, Chang YL, Pan SH, Wang WL, Hong TM, ' 'Yang PC. Tid1-L inhibits EGFR signaling in lung adenocarcinoma by ' 'enhancing EGFR Ubiquitinylation and degradation. Cancer Res. ' '2013;73:4009–19.', 'journal-title': 'Cancer Res'}, { 'key': '2435_CR49', 'doi-asserted-by': 'crossref', 'first-page': '150', 'DOI': '10.1186/s12931-014-0150-x', 'volume': '15', 'author': 'K Takashima', 'year': '2014', 'unstructured': 'Takashima K, Matsushima M, Hashimoto K, Nose H, Sato M, Hashimoto N, ' 'Hasegawa Y, Kawabe T. Protective effects of intratracheally administered ' 'quercetin on lipopolysaccharide-induced acute lung injury. Respir Res. ' '2014;15:150.', 'journal-title': 'Respir Res'}], 'container-title': 'Journal of Nanobiotechnology', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12951-024-02435-2.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s12951-024-02435-2/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12951-024-02435-2.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 4, 12]], 'date-time': '2024-04-12T13:06:13Z', 'timestamp': 1712927173000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-024-02435-2'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 4, 12]]}, 'references-count': 49, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2024, 12]]}}, 'alternative-id': ['2435'], 'URL': 'http://dx.doi.org/10.1186/s12951-024-02435-2', 'relation': {}, 'ISSN': ['1477-3155'], 'subject': [ 'Pharmaceutical Science', 'Applied Microbiology and Biotechnology', 'Biomedical Engineering', 'Molecular Medicine', 'Medicine (miscellaneous)', 'Bioengineering'], 'container-title-short': 'J Nanobiotechnol', 'published': {'date-parts': [[2024, 4, 12]]}, 'assertion': [ { 'value': '15 October 2023', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '22 March 2024', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '12 April 2024', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'The study involving SARS-CoV-2 was approved by the National Taiwan University ' 'Hospital Research Ethics Committee (202002002RIND).', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'All of the mouse experiments were approved by the Institutional Animal Care and ' 'Use Committee (IACUC) of Chang Gung University (IACUC approval no.: CGU110-015) ' 'and Chang Gung Memorial Hospital (IACUC approval no.: 2020121704).', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The authors declare no competing interests.', 'order': 5, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '169'}

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