TLR7-Adjuvanted Ionizable Lipid Nanoparticles for mRNA Vaccine Delivery

Apr 25, 2025The AAPS journal

Ionizable Lipid Nanoparticles with TLR7 Boosters for Delivering mRNA Vaccines

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Abstract

CL347-SM102 lipid nanoparticles exhibited particle sizes of less than 150 nm and mRNA encapsulation efficiency of greater than 95%.

Ionizable lipid nanoparticles (LNPs) allow for the intracellular delivery of mRNA vaccines and hydrophobic TLR7 adjuvants.
The lipid-based adjuvant CL347 selectively stimulates the TLR7 receptor, which is crucial for immune response activation.
In vivo studies indicated a two-fold increase in IFN-γ producing CD4 and CD8 T cells in lymphoid organs after immunization with adjuvanted LNPs.
Human immune cells treated with adjuvanted LNPs showed significantly higher CD40 expression and increased secretion of pro-inflammatory cytokines IL-6 and IFN-γ compared to those treated with non-adjuvanted LNPs.
These findings highlight the potential of ionizable LNPs for effective delivery of both mRNA and adjuvants in vaccine development.

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Ionizable lipid nanoparticles (LNPs) are clinically relevant non-viral vectors that allow intracellular delivery of mRNA vaccines to immune cells. To fight against notorious pathogens and cancer, mRNA vaccines necessitate the addition of an adjuvant to induce strong and durable cell-mediated immune responses. Adjuvants that stimulate Toll-like receptor 7 (TLR7) induce the secretion of type I interferons and proinflammatory cytokines, vital for generating strong immune responses. However, the intracellular delivery of TLR7 adjuvants to precisely stimulate the endosomal TLR7 receptor remains a huge challenge. This issue can be addressed by exploiting ionizable LNP platforms, which can encapsulate and carry mRNA vaccines and small molecule hydrophobic adjuvants to immune cells. CL347 is a potent lipid-based adjuvant that selectively stimulates the TLR7 receptor. In this study, we developed ionizable LNPs incorporating SM102 and CL347 adjuvant as the ionizable lipid and TLR7 adjuvant, respectively. CL347-SM102 LNPs exhibited particle sizes of less than 150 nm with spherical morphology and mRNA encapsulation efficiency of greater than 95%. In vivo studies showed a two-fold increase in IFN-γ producing CD4 and CD8 T cells in the lymphoid organs of the mice immunized with adjuvanted LNPs compared to the non-adjuvanted LNPs. Human PBMCs treated with adjuvanted LNPs exhibited significantly higher CD40 expression and pro-inflammatory cytokine (IL-6 and IFN-γ) secretion than non-adjuvanted LNPs. Together, these results suggest the potential of ionizable LNPs as a platform for concurrent delivery of mRNA and adjuvants for prophylactic and therapeutic vaccine applications.

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TLR7-Adjuvanted Ionizable Lipid Nanoparticles for mRNA Vaccine Delivery

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