Versatile lipoparticles for the co-delivery of TLR3 and TLR7/8 ligands as vaccine adjuvants: in vitro and in vivo evaluations

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Recent subunit vaccines based on purified protein antigens have shown reduced immunogenicity and efficacy, highlighting the need for adjuvants to improve the level and quality of the induced immune responses. Toll-like receptors (TLR) are innate immunity receptors that represent promising targets for the development of agonist-based vaccine adjuvants. Combinations of TLR ligands represent an attractive strategy for developing better adjuvants, but remain underexplored due to technical difficulties related to the co-delivery of molecules with distinct physicochemical properties. In this study, we designed LipoParticles based on a polylactic acid (PLA) core with a lipid envelope to co-deliver 3M052, a small molecule agonist of TLR7/8, and Poly (I:C), a synthetic dsRNA that activates TLR3. In vitro, the coordinated activation of the two TLR pathways by these LipoParticles was found more effective than single agonists in stimulating bone marrow-derived macrophages (BMDMs), as evidenced by the increased secretion of several cytokines, such as IL-12p70, TNF-α and IL-1β, and the induction of complementary clusters of immunity gene. Cytokine profiling and transcriptomic analysis also showed that the co-stimulation of TLR3 and TLR7/8 specifically induced inhibitory factors, such as IL-10, IL-19 and IRAK-M. Importantly, following in vivo immunization of mice, the dual formulation appears to modulate the immune profile, with an improved Th1 polarization assessed by quantifying type II IFN secreted by splenocytes, which is a promising finding for vaccine development. Overall, our results validate the efficacy of our LipoParticles as a delivery platform for combinations of TLR ligands. This new carrier will be useful for testing combinations of adjuvant molecules and for selecting those capable of boosting antigen-specific immunity, as this appears to be more complex to achieve than anticipated.

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