Covalent Conjugation of Small-Molecule Adjuvants to Nanoparticles Induces Robust Cytotoxic T Cell Responses via DC Activation

Abstract

Specific recognitions of pathogen associated molecular patterns by Toll-like receptors (TLRs) initiate dendritic cell (DC) activation, which is critical for coordinating innate and adaptive immune responses. Imidazoquinolines as small-molecule TLR7 agonists often suffer from prompt dissemination and short half-life in the bloodstream, preventing their localization to the corresponding receptors and effective DC activation. We postulated that covalent incorporation of imidazoquinoline moieties onto the surface of biocompatible nanoparticles (∼30 nm size) would enhance their chemical stability, cellular uptake efficiency, and adjuvanticity. The fully synthetic adjuvant-nanocomplexes led to successful DC activation at lower nanomolar doses compared with free small-molecule agonists. Once a model antigen such as ovalbumin was used for immunization, we found that the nanocomplexes promoted an unusually strong cytotoxic T lymphocyte response, revealing their unique immunostimulatory capacity benefiting from multivalency and efficient transport to endosomal TLR7.

Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance

“…To our knowledge, this is the first report of selective antigen delivery to antigen-presenting cells localizing at tumor tissues. Interestingly, this modification improved tumor sensitivity to T cell-mediated immunity, thereby rendering this approach different from conventional lymph node-targeted delivery of antigens and TLR ligands to reinforce antitumor T cell-mediated immunity (36,69). A TLR agonist was also essential in the present combination immunotherapy, as macrophages that engulf antigens but are inactive cannot efficiently present antigens to T cells.…”

Systemic Immunotherapy with Micellar Resiquimod–Polymer Conjugates Triggers a Robust Antitumor Response in a Breast Cancer Model

“…[ 34 ] The formulation of immunomodulating nanocarriers can be via physical encapsulation of the immunomodulator(s) into NPs, through covalent attachment onto preformed NPs, or covalent attachment to surfactant‐like molecules/polymers which are then transformed into NPs. [ 14,21,35–39 ]…”

N‐Carboxyanhydride Polymerization of Glycopolypeptides That Activate Antigen‐Presenting Cells through Dectin‐1 and Dectin‐2

“…[13] Notably, TLR agonists on polymeric scaffolds have shown enhanced potency, and liposomal nanostructure formulations are undergoing preclinical evaluation. [34,35] With this novel platform, we intend to explore how Dec-1 and -2 agonists perform in related supramolecular structures.…”