Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines PMID: 37365276

ADC Targets in Oncology

2026-04-10

Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines

Nat Nanotechnol. 2023 Jun 26. doi: 10.1038/s41565-023-01404-4.

Xuexiang Han ^# ¹ , Mohamad-Gabriel Alameh ^# ² ³ ⁴ , Kamila Butowska ¹ ⁵ , James J Knox ⁶ , Kendall Lundgreen ⁷ , Majed Ghattas ⁸ , Ningqiang Gong ¹ , Lulu Xue ¹ , Ying Xu ⁹ , Marc Lavertu ⁸ , Paul Bates ⁷ , Junchao Xu ¹⁰ , Guangjun Nie ¹⁰ , Yi Zhong ¹¹ , Drew Weissman ¹² ¹³ , Michael J Mitchell ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
2. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3. Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4. Department of Bioengineering, George Mason University, Fairfax, VA, USA.
5. Intercollegiate Faculty of Biotechnology, University of Gdańsk & Medical University of Gdańsk, Gdańsk, Poland.
6. Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA.
7. Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
8. Department of Chemical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada.
9. Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA.
10. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, People's Republic of China.
11. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
12. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
13. Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
14. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
15. Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
16. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
17. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
18. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
19. Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
# Contributed equally.

Abstract

Lipid nanoparticle (LNP)-formulated messenger RNA (mRNA) vaccineare a promising platform to prevent infectious diseases as demonstrated by the recent success of SARS-CoV-2 mRNA vaccines. To avoid immune recognition and uncontrolled inflammation, nucleoside-modified mRNA is used. However, such modification largely abrogates the innate immune responses that are critical to orchestrating robust adaptive immunity. Here we develop an LNP component-an Adjuvant lipidoid-that can enhance the adjuvanticity of mRNA-LNP vaccines. Our results show that partial substitution of ionizable lipidoid with Adjuvant lipidoid not only enhanced mRNA delivery, but also endowed LNPs with Toll-like Receptor 7/8-agonistic activity, which significantly increased the innate immunity of the SARS-CoV-2 mRNA-LNP vaccine with good tolerability in mice. Our optimized vaccine elicits potent neutralizing antibodies against multiple SARS-CoV-2 pseudovirus variants, strong Th1-biased cellular immunity, and robust B cell and long-lived plasma cell responses. Importantly, this Adjuvant lipidoid substitution strategy works successfully in a clinically relevant mRNA-LNP vaccine, demonstrating its translational potential.