Abstract
The transformational impact of bioorthogonal chemistries has inspired new strategies for the in vivo synthesis of bioactive agents through non-natural means. Among these, palladium (Pd) catalysts have played a prominent role in the growing subfield of bioorthogonal catalysis by producing xenobiotics and uncaging biomolecules in living systems. However, delivering catalysts selectively to specific cell types still lags behind catalyst development. Here we have developed a bio-artificial device consisting of cancer-derived exosomes loaded with Pd catalysts by a method that enables the controlled assembly of Pd nanosheets directly inside the vesicles. This hybrid system mediates Pd-triggered dealkylation reactions in vitro and inside cells and displays preferential tropism for their progenitor cells. The use of Trojan exosomes to deliver abiotic catalysts into designated cancer cells creates the opportunity for a new targeted therapy modality: exosome-directed catalyst prodrug therapy, whose first steps are presented herein with the cell-specific release of the anticancer drug panobinostat.