Ultrasmall silica nanoparticles directly ligate the T cell receptor complex

Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):285-291. doi: 10.1073/pnas.1911360117. Epub 2019 Dec 23.


The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αβ TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain-associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.

Keywords: T cell activation; TCR:CD3 complex; ultrasmall silica nanoparticle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD28 Antigens / metabolism
  • CD3 Complex / chemistry
  • CD3 Complex / drug effects
  • Cell Proliferation / drug effects
  • Humans
  • Interleukin-2 / metabolism
  • Lymphocyte Activation / drug effects*
  • Models, Molecular
  • Nanoparticles / chemistry*
  • Phosphorylation
  • Receptor-CD3 Complex, Antigen, T-Cell / chemistry
  • Receptor-CD3 Complex, Antigen, T-Cell / drug effects*
  • Receptor-CD3 Complex, Antigen, T-Cell / genetics
  • Receptor-CD3 Complex, Antigen, T-Cell / metabolism*
  • Signal Transduction / immunology
  • Silicon Dioxide / chemistry*
  • Silicon Dioxide / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • CD28 Antigens
  • CD3 Complex
  • Interleukin-2
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Silicon Dioxide