Engineering Receptor-Directed Intracellular Palladium Catalysis

Directing abiotic chemical activity toward cells defined by surface receptors remains difficult because a metal complex must combine recognition with reactivity in biological media. Integrin-, epidermal growth factor receptor (EGFR)-, and CD44-binding peptides were joined to a bis(histidine) Pd(II)-binding zinc-finger scaffold to create three receptor-directed Pallado-fingers. Each construct retained depropargylation reactivity in an equimolar cell-free assay. In paired cell models, the integrin- and EGFR-directed complexes showed >2.5-fold greater cellassociated fluorescence in receptor-enriched cells, while the CD44-directed complex showed 1.45-fold enrichment. Antibody profiling, receptor competition, mixed-cell discrimination, and αvβ3 knockdown connected this bias to receptor engagement. Receptor-enriched cells then generated greater fluorescence from a masked dye, and cell-associated-Pd-normalized apparent turnover numbers of 3.81–5.76 supported catalysis at the whole-cell level. The same design increased nuclear accumulation of a masked nuclear localization sequence and enhanced the Annexin V response of propargyl-protected temporin in A549 cells. These results establish a modular route from surface recognition to receptor-biased intracellular unmasking.