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