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

Angela R. Corrigan; Shin Foong Ngiow; Maura Statzu; Amie Albertus; María Betina Pampena; Jayme M.L. Nordin; Stephen D. Carro; Justin L. Harper; Rachelle L. Stammen; Jennifer Wood; Houping Ni; Justin Su; Marziyeh Hajialyani; Vladimir V. Shuvaev; Víctor Alcalde; Mohammed-Alkhatim A. Ali; Jacob T. Hamilton; Rajesvaran Ramalingam; Vincent H. Wu; Mirko Paiardini; Drew Weissman; E. John Wherry; Edward F. Kreider; Michael R. Betts

doi:10.1126/sciimmunol.aec3436

ImmunologyScience ImmunologyMay 29, 2026

Peer-reviewed journal article

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

Angela R. Corrigan iD, Shin Foong Ngiow iD, Maura Statzu iD, Amie Albertus iD, María Betina Pampena iD, Jayme M.L. Nordin iD, Stephen D. Carro iD, Justin L. Harper iD, Rachelle L. Stammen iD, Jennifer Wood iD, Houping Ni iD, Justin Su iD, Marziyeh Hajialyani iD, Vladimir V. Shuvaev iD, Víctor Alcalde iD, Mohammed-Alkhatim A. Ali iD, Jacob T. Hamilton iD, Rajesvaran Ramalingam, Vincent H. Wu iD, Mirko Paiardini iD, Drew Weissman iD, E. John Wherry iD, Edward F. Kreider iD, Michael R. Betts iD

Abstract

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-LNP) can specifically target and deliver mRNA to CX3CR1+ Teff cells in vitro and in vivo. In mice, fractalkine-conjugated LNP target up to 90% of blood and splenic Teff cells, and delivery of IL-2-encoding mRNA to Teff cells enables robust exogenous IL-2 secretion. In rhesus macaques, fractalkine-conjugated mRNA-LNP 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-LNP for effective and efficient transient in vivo modification of Teff cells.

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