ChemCell: Chemical Tethering of Large Biomolecules to Cell Surfaces through Diels-Alder Ligation

ABSTRACT Chemical engineering of cellular surfaces offers a powerful tool to endow cells with new properties and functions, yet methods for adding complex biomolecules to cell membranes remain underdeveloped. While technologies for targeted degradation of cell surface components are advancing, few approaches exist that allow efficient attachment of large biomolecules. To address this, we introduce ChemCell technology—a platform for non-genetic surface engineering of cells via metabolic installation of trans-cyclooctene (TCO) groups. These TCO groups undergo rapid and selective reactions with tetrazine-modified biomolecules, enabling the efficient tethering of diverse functional groups. This method allows for the precise attachment of proteins, peptides, enzymes, oligonucleotides, therapeutic antibodies, and large protein complexes to cell surfaces, expanding the toolbox for cellular modification and offering new possibilities for cell-based therapies and diagnostics.