In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles
Menée à l'aide de lignées cellulaires, de modèles murins et de cellules mononucléées du sang périphérique de patients atteints d'une leucémie ou d'un lymphome, cette étude met en évidence l'intérêt thérapeutique de nanoparticules lipidiques capables de cibler le point de contrôle immunitaire NKG2 des cellules NK via des ligands biparatopiques et de délivrer à ces cellules un ARN messager permettant de générer un récepteur chimérique ciblant les cellules cancéreuses ou les cellules immunitaires autoréactives
Targeted lipid nanoparticles (LNPs) offer a nonviral approach for in vivo cell engineering but efficient programming of natural killer (NK) cells remains underexplored. Here we develop NK cell-targeted LNPs (NtLNPs) using engineered biparatopic NK cell ligands to drive receptor-specific uptake and mRNA delivery. Lead NtLNPs achieve up to ~80% NK cell transfection with minimal off-target effects in mice. Systemic delivery of chimeric antigen receptor (CAR) mRNA using NtLNPs generates CAR NK cells in vivo. CD19-targeted CAR NKs completely deplete circulating B cells in healthy mice and CD3-targeted CAR NKs eliminate nearly all autoreactive T cells in an autoimmune hepatitis model, highlighting a potential advantage over CAR T therapies for T cell-driven disease. In solid tumors, NtLNPs targeting the inhibitory checkpoint NKG2A enhance antitumor efficacy by relieving Qa-1b-mediated immunosuppression. Lastly, we optimized NtLNPs for in vivo engineering of human CAR NK cells, enabling regression of two humanized hematologic malignancy models and establishing NtLNPs as a modular immunotherapy system.
Nature Biotechnology , article en libre accès, 2026