Click‐and‐Release Formation of Urea Bonds in Living Cells Enabled by Micelle Nanoreactors

The development of innovative strategies enabling chemical reactions in living systems is of great interest for exploring and manipulating biological processes. Herein, we present a pioneering approach based on both bioorthogonal and confined chemistry for intracellular drug synthesis. Exploiting a click-to-release reaction, we engineered nanoparticles capable of synthesizing drugs within cellular environments through bioorthogonal reactions with cyclooctynes. Proof of concept experiments showed that this new approach could be successfully applied to the synthesis of the FDA-approved Sorafenib within cancer cells. The integration of bioorthogonal and confined chemistry not only offers exciting prospects for advancing therapeutic strategies but also opens up new avenues for exploring non-natural reactions within living systems. This innovative approach represents a fundamental extension of the biorthogonal chemistry concept and holds great promise for pioneering developments in therapeutic applications.