Science immunology · 2026
In vivo reprogramming of cytotoxic effector CD8 T cells via fractalkine-conjugated mRNA-LNPs.
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Corrigan Angela R, Ngiow Shin Foong, Statzu Maura, Albertus Amie, Pampena M Betina, Nordin Jayme M L, Carro Stephen D, Harper Justin, Stammen Rachelle L, Wood Jennifer, Ni Houping, Su Justin, Hajialyani Marziyeh, Shuvaev Vladimir V, Alcalde Victor, Ali Mohammed-Alkhatim A, Hamilton Jacob T, Ramalingam Rajesvaran, Wu Vincent H, Paiardini Mirko, Weissman Drew, Wherry E John, Kreider Edward F, Betts Michael R
Аннотация
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 mRNA-LNPs targeted up to 95% of blood and splenic Teff cells. In addition, delivery of IL-2-encoding mRNA and human CD62L-encoding mRNA to mouse Teff cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood Teff cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood Teff cells and detection of human CD62L+ Teff cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of Teff cells.