In vivo reprogramming of cytotoxic effector CD8+ T cells via fractalkine-conjugated mRNA LNPs

Selective in vivo reprogramming of cytotoxic effector CD8+ T (Teff) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA LNPs) can specifically target and deliver mRNA to CX3CR1+ Teff cells in vitro and in vivo. In mice, fractalkine-conjugated LNPs target up to 90% of blood and splenic Teff cells, and delivery of IL-2 encoding mRNA to Teff cells enables robust IL-2 secretion. In rhesus macaques, fractalkine-conjugated mRNA LNPs target up to 100% of peripheral blood Teff cells and delivery of CD62L-mRNA enables transient CD62L expression. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA LNPs for effective and efficient transient in vivo modification of Teff cells.