Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles

Biomater Sci. 2018 Dec 18;7(1):113-124. doi: 10.1039/c8bm01208c.


We sought to develop a nanoparticle vehicle that could efficiently deliver small molecule drugs to target lymphocyte populations. The synthesized amphiphilic organic ligand-protected gold nanoparticles (amph-NPs) were capable of sequestering large payloads of small molecule drugs within hydrophobic pockets of their ligand shells. These particles exhibit membrane-penetrating activity in mammalian cells, and thus enhanced uptake of a small molecule TGF-β inhibitor in T cells in cell culture. By conjugating amph-NPs with targeting antibodies or camelid-derived nanobodies, the particles' cell-penetrating properties could be temporarily suppressed, allowing targeted uptake in specific lymphocyte subpopulations. Degradation of the protein targeting moieties following particle endocytosis allowed the NPs to recover their cell-penetrating activity in situ to enter the cytoplasm of T cells. In vivo, targeted amph-NPs showed 40-fold enhanced uptake in CD8+ T cells relative to untargeted particles, and delivery of TGF-β inhibitor-loaded particles to T cells enhanced their cytokine polyfunctionality in a cancer vaccine model. Thus, this system provides a facile approach to concentrate small molecule compounds in target lymphocyte populations of interest for immunotherapy in cancer and other diseases.

MeSH terms

  • Animals
  • Cells, Cultured
  • Drug Delivery Systems*
  • Female
  • Gold / chemistry*
  • Gold / pharmacokinetics
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacokinetics
  • Metal Nanoparticles / chemistry*
  • Mice, Inbred C57BL
  • Small Molecule Libraries / administration & dosage*
  • Small Molecule Libraries / pharmacology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / antagonists & inhibitors*


  • Immunoconjugates
  • Small Molecule Libraries
  • Transforming Growth Factor beta
  • Gold