Jiawu Wan, Caiqian Wang, Zongmei Wang, Lingli Wang, Haoran Wang, Ming Zhou, Zhenfang Fu and Ling Zhao

PNAS, October 22, 2024, 121 (44) e2406434121. https://doi.org/10.1073/pnas.2406434121

Significance

Integrating adjuvants into circular RNAs (circRNAs) demonstrates the prospect of developing circRNA vaccines and adjuvants, enabling circRNA encoding antigens and adjuvants can codeliver both components to the same antigen-presenting cell in a straightforward formulation. Here, we designed a general strategy to improve the magnitude and breadth of the antibody response induced by circRNA vaccines and remodeled the immune microenvironment of lymph nodes by integrating CXCL13 and antigens into circRNAs for coexpression. The targeted modification of the lipid nanoparticle (LNP) surface with antibodies effectively improves the lyophilization stability, enabling long-term preservation of the vaccine. This study demonstrates that CXCL13 based on the circRNA-tLNPs can provide broad immune stimulation in vaccines against multiple pathogens.

Abstract

Antibody responses induced by current vaccines for influenza and SARS-CoV-2 often lack robust cross-reactivity. As hubs where diverse immune cells converge and interact, the alterations in the immune microenvironment within lymph nodes (LNs) are intricately linked to immune responses. Herein, we designed a lipid nanoparticle (LNP) loaded with circular RNA (circRNA) and targeted to LNs, in which CXCL13 was directly integrated into antigen-encoding circRNA strands. We demonstrated that CXCL13 alters the transcriptomic profiles of LNs, especially the upregulation of IL-21 and IL-4. Meanwhile, CXCL13 promotes the formation of germinal center and elicits robust antigen-specific T cell responses. With the codelivery of CXCL13 and the antigen, CXCL13 enhances cross-reactive antibodies against influenza virus and SARS-CoV-2, achieving protection against both homologous and heterologous influenza virus challenges in a mouse model. Notably, the targeted modification of LNP surfaces with antibodies helps address some of the challenges associated with lyophilized LNP vaccines, which is crucial for the long-term storage of LNP-circRNA vaccines. Overall, the circRNA-based antigen-CXCL13 coexpression system developed herein provides a simple and robust platform that enhances the magnitude and breadth of antibody responses against multiple viral glycoproteins, highlighting the potential utility of CXCL13 in inducing broad immune responses.

原文链接： https://doi.org/10.1073/pnas.2406434121