bims-hummad Biomed News
on Humanised mouse models of autoimmune disorders
Issue of 2026–10–18
two papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles.
  2. Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism.
  1. Nat Biotechnol. 2026 Oct 13.
    In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles.
    Yuang Chen, Julia Monkovic, Haseeb Mughal, Binlong Chen, Elina Thadhani, Patrick McMullen, Ava Self, Yuxuan Chen, Yizong Hu, Samuel Detmer, Min Chen, Anna Lapteva, Ria Kamat, Ashley Vernon, Robert Langer, Daniel G Anderson.
      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.
    DOI:  https://doi.org/10.1038/s41587-026-03310-1
  2. Nature. 2026 Oct 14.
    Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism.
    D Alejandro Canaria, Trang T T Nguyen, Huang Huang, Hui Xu, Lili Yue, Yongyao Fu, Hoa Truong, Kerul Patel, Weimei Xing, Jayamary Divya Ravichandar, Cong Xing, Aron L Martin, George Delidakis, Sylvia Wong, Andrew Pae, Yu Yu, Ramsay Macdonald, Zhiyu Huang, Meagan C Main, Amanali Rodriguez, Xiaoli Lin, Maria L Mouchess, Magdeleine Hung, Ellen M McGlinchey, Lei Chen, Nicole Schirle Oakdale, Brian Carr, Megan L Koleske, Chingwei V Lee, Chen Chen, Tangsheng Yi.
      Interleukin-10 (IL-10) is a central anti-inflammatory cytokine that suppresses immune responses in myeloid cells but can also activate T cells, limiting its therapeutic use in chronic inflammatory diseases owing to narrow efficacy windows and dose-limiting toxicities1-5. Here we show that myeloid and T cells differ in their dependence on JAK-family kinase pairing for IL-10 signalling and function. We took advantage of this differential kinase dependence to engineer a tetravalent nanobody-based myeloid-selective IL-10 receptor agonist (msIL-10R agonist) that fully recapitulates IL-10's potent suppression of monocytes, macrophages and dendritic cells while avoiding stimulation of T cells. Cryo-electron microscopy structural analysis reveals a distinct receptor cross-linking geometry of the msIL-10R agonist compared with native IL-10 family cytokines. This tetravalent architecture renders signalling strictly TYK2-dependent and highly sensitive to IL-10Rα and IL-10Rβ receptor abundance, thereby conferring selective activity in myeloid cells. This msIL-10R agonist reduces inflammation in humanized mouse models of lipopolysaccharide challenge, delayed-type hypersensitivity and colitis. A humanized version exhibits IgG-like pharmacokinetics, sustained receptor occupancy and durable myeloid suppression up to 30 days without T cell activation or haematological toxicities in non-human primates. These findings establish a geometry-based strategy for achieving cell-type-selective cytokine signalling and identify the msIL-10R agonist as a therapeutic candidate for myeloid-driven inflammatory diseases, including inflammatory bowel diseases.
    DOI:  https://doi.org/10.1038/s41586-026-11176-1
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