Imidazole‐Based Synthetic Lipidoids for In Vivo mRNA Delivery into Primary T Lymphocytes

Abstract

Engineering Tlymphocytes is an emerging approach in av ariety of biomedical applications.H owever,d elivering large biologics to primary Tl ymphocytes directly in vivo is technically challenging due to the lowt ransfection efficacy. Herein, we investigated al ibrary of synthetic lipid-like molecules (lipidoids) for their capability of delivering mRNA into primary Tl ymphocytes both ex vivo and in vivo.W e initially screened al ibrary with al arge structural variety of lipidoids ex vivo and identified imidazole-containing lipidoids that are particularly potent in Tl ymphocytes transfection. We further optimizedl ipidoid structures by constructing and screening ad etailed lipidoid library containing imidazole or imidazole analogues to perform astructure-activity correlation analysis.U sing the lead lipidoid as ad elivery vehicle for Cre mRNAi nvivo through intravenous injection, we achieved 8.2 %gene recombination in mouse Tlymphocytes.

mRNA vaccines for infectious diseases: principles, delivery and clinical translation

“…In addition to the search for improved efficacy, a growing interest in improving the specificity of delivery, particularly for vaccines and immunotherapies, has spurred efforts to target immune cells. Lipids containing polycyclic adamantane tails, such as 11-A-M 58 , or those containing cyclic imidazole heads, such as 93-O17S 59 , have been designed to target T cells in vivo. Although the mechanism is unclear, the cyclic groups of these lipids are crucial for targeting T cells.…”

Nanoscale delivery platforms for RNA therapeutics: Challenges and the current state of the art

“…In a recent example, Parayath et al used anti-CD8 antibodyconjugated PBAE nanoparticles to deliver mRNA-encoding chimeric antigen receptors (CAR) to circulating T cells in vivo; the resulting transient CAR T cells were able to reduce tumor burden and improve outcome in multiple tumor models. 79 These results, among other studies that have developed platforms for T cell-specific delivery in vivo, 134,155 open the possibility for off-the-shelf reagents for directly engineering the immune system in vivo. Delivery to organs, ll such as the eye and the brain, that have specialized barriers in addition to circulation and cytoplasmic delivery, has been achieved primarily through local administration, although some studies have achieved delivery to the brain parenchyma upon systemic administration.…”

The landscape of mRNA nanomedicine

“…One strategy for cell type-specific mRNA delivery is developing LNPs or polymeric nanoparticles with formulations optimized for the specific target cell type. For instance, well-optimized 149,150 , biomimetic 151 and imidazole-based 152 LNPs and polymers 104,108 have been used for the targeted delivery of mRNAs to T cells for cancer immunotherapy, and selective delivery of mRNAs to leukocytes 153 has also been achieved. Another strategy is using cell-specific ligands.…”