Targeting rapidly cycling receptors CD2 and CD7 increases nanoparticle delivery to primary CD4+ T cells
Abstract T cells are critically important to many diseases but are traditionally difficult to transfect. We hypothesise that the delivery of therapeutic cargo to T cells can be improved by targeting nanoparticles to surface receptors that undergo rapid receptor-mediated endocytosis. Using an internalisation assay that labelled intracellular and surface proteins with different fluorophores, we find that CD2 and CD7 exhibit significantly higher internalisation than other T cell receptors, such as CD3 or CD4. Targeting CD2 and CD7 improves nanoparticle internalisation by non-stimulated, primary CD4 + T cells and enhances the specificity of association to CD4 + T cells. Similarly, functionalising mRNA-lipid nanoparticles with antibodies targeting CD2 or CD7 enhances mRNA delivery to CD4 + T cells in vitro. Importantly, targeting CD2 or CD7 enables efficient lipid nanoparticle-mediated delivery of mRNA to T cells in blood and lymphoid tissue in vivo, demonstrating that targeting T cell receptor endocytosis can enhance nanoparticle-mediated drug delivery to T cells.
Authors
- Frank S Caruso (ORCID: https://orcid.org/0000-0002-0197-497X)
- Merle Dayton
- Marcel Doerflinger (ORCID: https://orcid.org/0000-0001-9159-3021)
- Haiyin Liu (ORCID: https://orcid.org/0000-0003-3103-6949)
- L J Wang
- Paula M. Cevaal (ORCID: https://orcid.org/0000-0003-4473-7904)
- Céline Gubser (ORCID: https://orcid.org/0000-0002-3588-3814)
- René P. M. Lafleur (ORCID: https://orcid.org/0000-0003-0026-3428)
- Sharon R. Lewin (ORCID: https://orcid.org/0000-0002-0330-8241)
- Stanislav Kan
- Robert De Rose (ORCID: https://orcid.org/0000-0003-4316-3910)
- Liana Mackiewicz (ORCID: https://orcid.org/0000-0002-4340-4975)
- Angus P. R. Johnston (ORCID: https://orcid.org/0000-0001-5611-4515)
- Matthew Faria (ORCID: https://orcid.org/0000-0003-1729-5813)
- Moore Chen (ORCID: https://orcid.org/0000-0002-4234-5117)
- Ammar Ali (ORCID: https://orcid.org/0009-0004-7753-8543)
- Jori Symons (ORCID: https://orcid.org/0000-0001-6560-1577)
- Christina Cortez-Jugo (ORCID: https://orcid.org/0000-0001-5341-175X)
- Michael Roche
- Abigail Tan
Institutions
- The Royal Melbourne Hospital (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Centre Hospitalier Universitaire Vaudois (CH)
- University Medical Center Utrecht (NL)
- Peter Doherty Institute (AU)
- Hôpital Orthopédique de la Suisse Romande (CH)
- BioNTech (Germany) (DE)
- Ardent Sound (United States) (US)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-01
- DOI
- https://doi.org/10.1038/s41467-026-74981-2
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- amfAR, The Foundation for AIDS Research
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Australian Centre for HIV and Hepatitis Virology Research
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- University of California, San Francisco
- Medical Research Council
- National Health and Medical Research Council