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Nanoparticle-Mediated In Situ Molecular Reprogramming of Immune Checkpoint Interactions for Cancer Immunotherapy.

التفاصيل البيبلوغرافية
العنوان: Nanoparticle-Mediated In Situ Molecular Reprogramming of Immune Checkpoint Interactions for Cancer Immunotherapy.
المؤلفون: Walters AA; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom., Santacana-Font G; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom., Li J; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom., Routabi N; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom., Qin Y; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom., Claes N; EMAT, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium., Bals S; EMAT, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium., Tzu-Wen Wang J; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom., Al-Jamal KT; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
المصدر: ACS nano [ACS Nano] 2021 Oct 22. Date of Electronic Publication: 2021 Oct 22.
Publication Model: Ahead of Print
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101313589 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1936-086X (Electronic) Linking ISSN: 19360851 NLM ISO Abbreviation: ACS Nano Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington D.C. : American Chemical Society
مستخلص: Immune checkpoint blockade involves targeting immune regulatory molecules with antibodies. Preclinically, complex multiantibody regimes of both inhibitory and stimulatory targets are a promising candidate for the next generation of immunotherapy. However, in this setting, the antibody platform may be limited due to excessive toxicity caused by off target effects as a result of systemic administration. RNA can be used as an alternate to antibodies as it can both downregulate immunosuppressive checkpoints (siRNA) or induce expression of immunostimulatory checkpoints (mRNA). In this study, we demonstrate that the combination of both siRNA and mRNA in a single formulation can simultaneously knockdown and induce expression of immune checkpoint targets, thereby reprogramming the tumor microenvironment from immunosuppressive to immunostimulatory phenotype. To achieve this, RNA constructs were synthesized and formulated into stable nucleic acid lipid nanoparticles (SNALPs); the SNALPs produced were 140-150 nm in size with >80% loading efficiency. SNALPs could transfect macrophages and B16F10 cells in vitro resulting in 75% knockdown of inhibitory checkpoint (PDL1) expression and simultaneously express high levels of stimulatory checkpoint (OX40L) with minimal toxicity. Intratumoral treatment with the proposed formulation resulted in statistically reduced tumor growth, a greater density of CD4+ and CD8+ infiltrates in the tumor, and immune activation within tumor-draining lymph nodes. These data suggest that a single RNA-based formulation can successfully reprogram multiple immune checkpoint interactions on a cellular level. Such a candidate may be able to replace future immune checkpoint therapeutic regimes composed of both stimulatory- and inhibitory-receptor-targeting antibodies.
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust
فهرسة مساهمة: Keywords: SNALP; immune checkpoint; immunotherapy; mRNA; siRNA
تواريخ الأحداث: Date Created: 20211022 Latest Revision: 20240220
رمز التحديث: 20240220
مُعرف محوري في PubMed: PMC8613910
DOI: 10.1021/acsnano.1c04456
PMID: 34677938
قاعدة البيانات: MEDLINE
الوصف
تدمد:1936-086X
DOI:10.1021/acsnano.1c04456