Microneedle-assisted genome editing: A transdermal strategy of targeting  NLRP3  by CRISPR-Cas9 for synergistic therapy of inflammatory skin disorders

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Abstract

Transdermal delivery of genome-editing agents by microneedle promotes the glucocorticoid therapy of inflammatory skin disorders.

Abstract

We report a dissolvable microneedle (MN) patch that can mediate transdermal codelivery of CRISPR-Cas9–based genome-editing agents and glucocorticoids for the effective treatment of inflammatory skin disorders (ISDs). The MN is loaded with polymer-encapsulated Cas9 ribonucleoprotein (RNP) targeting NLRP3 and dexamethasone (Dex)–containing polymeric nanoparticles. Upon insertion into the skin, the MN can be dissolved quickly to release two types of nanoformulations, which are subsequently internalized by keratinocytes and surrounding immune cells to exert their therapeutic effects in the inflammatory subcutaneous layers. Thus, the MN-enabled transdermal codelivery of Cas9 RNP nanocomplexes and Dex nanoparticles result in the disruption of subcutaneous intracellular NLRP3 inflammasomes, which is demonstrated to be critical to alleviate skin inflammations and contributes to glucocorticoid therapy in mouse models of ISDs, including psoriasis and atopic dermatitis. Our study offers innovative insights into the rational design of transdermal delivery systems and defines an effective therapeutic option for the treatment of ISDs.

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Inflammasomes: mechanism of assembly, regulation and signalling.

Petr Broz, Vishva Dixit (2016)

Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.

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Atopic dermatitis

Stephan Weidinger, Kenji Kabashima, Alan D. Irvine … (2018)

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.

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NLRP3 inflammasome and its inhibitors: a review

Bo-zong Shao, Zhe-Qi Xu, Bin-ze Han … (2015)

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.

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Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: March 2021

Publication date (Electronic): 10 March 2021

Volume: 7

Issue: 11

Electronic Location Identifier: eabe2888

Affiliations

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: pingy@ 123456zju.edu.cn

Author information

Tao Wan http://orcid.org/0000-0002-8299-8921

Qi Pan http://orcid.org/0000-0002-1852-1387

Yuan Ping http://orcid.org/0000-0003-2571-7721

Article

Publisher ID: abe2888

DOI: 10.1126/sciadv.abe2888

PMC ID: 7946375

PubMed ID: 33692106

SO-VID: bed9f342-a964-462e-a078-e8cc60159c0b

Copyright © Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 22 September 2020

Date accepted : 26 January 2021

Funding

Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82073779,81872807

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Copyeditor Anne Suarez

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Microneedle-assisted genome editing: A transdermal strategy of targeting NLRP3 by CRISPR-Cas9 for synergistic therapy of inflammatory skin disorders

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Biomarkers for Inflammatory Lung Disease

Most cited references 36

Inflammasomes: mechanism of assembly, regulation and signalling.

Atopic dermatitis

NLRP3 inflammasome and its inhibitors: a review

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