Targeting rapidly cycling receptors CD2 and CD7 increases nanoparticle delivery to primary CD4+ T cells

Abstract T cells are critically important to many diseases but are traditionally difficult to transfect. We hypothesise that the delivery of therapeutic cargo to T cells can be improved by targeting nanoparticles to surface receptors that undergo rapid receptor-mediated endocytosis. Using an internalisation assay that labelled intracellular and surface proteins with different fluorophores, we find that CD2 and CD7 exhibit significantly higher internalisation than other T cell receptors, such as CD3 or CD4. Targeting CD2 and CD7 improves nanoparticle internalisation by non-stimulated, primary CD4 + T cells and enhances the specificity of association to CD4 + T cells. Similarly, functionalising mRNA-lipid nanoparticles with antibodies targeting CD2 or CD7 enhances mRNA delivery to CD4 + T cells in vitro. Importantly, targeting CD2 or CD7 enables efficient lipid nanoparticle-mediated delivery of mRNA to T cells in blood and lymphoid tissue in vivo, demonstrating that targeting T cell receptor endocytosis can enhance nanoparticle-mediated drug delivery to T cells.