Cellular communication in the immune system relies on the precise spatial organization of biological cues, proteins, and receptor ligands presented at specific densities and spacings to trigger appropriate cellular responses. In the context of T-cell-mediated immunity, this is particularly relevant to cellular immunotherapy (adoptive cell therapy), where a patient's own T-cells are harvested, activated via antigen–MHC complexes presented on their surface, and expanded before being returned to the patient to target cancer cells. Low-affinity CD8+ T-cells are of particular therapeutic interest, as they can generate more robust secondary recall responses that prolong therapeutic effect, but they are more difficult to selectively activate and expand than their high-affinity counterparts. Multimerized presentation of tumour-associated antigens on synthetic scaffolds is one route to potentiating these low-affinity T-cells; however, existing synthetic platforms (covalent polymers, microbeads, metal nanoparticles, DNA nanostructures) have generally lacked the stability and systematic spatial control needed to precisely tune ligand density and spacing in a cellular environment.
SupraCODE was conceived to address this gap by developing supramolecular block copolymers, based on squaramide chemistry, capable of presenting bioactive antigen complexes (the H2-Kb-OVA peptide) with defined spacing and density along a filamentous scaffold. While supramolecular polymer chemistry has advanced considerably over the past two decades, enabling sequence-defined 1D and 2D nanostructures with precise dimensions, this progress has occurred largely in organic solvents, whereas biological application requires assembly and stability in water. SupraCODE's overall objective was therefore twofold: first, to establish design rules for kinetically controlled, sequence-defined supramolecular polymerization of squaramide-based building blocks in aqueous solution; and second, to apply this platform to spatially control antigen presentation and investigate its effect on T-cell receptor activation, with a view to informing future strategies in cancer immunotherapy.
The project's pathway to impact was designed to proceed from fundamental supramolecular chemistry and living supramolecular polymerization, through the construction of antigen-decorated supramolecular block copolymers, to biological validation of their effect on CD8+ T-cell activation, in collaboration with immunology expertise at Leiden University. During execution, the fundamental chemistry stage proved substantially more complex than anticipated, and the project's scientific contribution consequently centred on establishing new, previously undescribed design principles for aqueous supramolecular polymerization, including pathway-controlled assembly, foldamer formation, supramolecular polymorphism, and fluorescence in squaramide systems. These fundamental insights are expected to provide the necessary foundation on which the originally envisaged biomaterials platform for immune cell activation can be built in future work.
