Biodialyzed Palladium catalysis enables bioorthogonal drug release to control epithelial progenitor cell differentiation

Flowing from the principles of bioorthogonality, the introduction of abiotic transition metals for the catalytic production of drugs at specific anatomical locations has carved new paths to face challenging diseases, including cancer. Despite ground-breaking advances in this area, the main barrier for the long-term application of bioorthogonal catalysis in medicine is catalyst inactivation by the surrounding environment. Herein we present a semipermeable membrane-inspired approach to separate the catalysts from the environment by incorporating them into a porous scaffold that minimizes interactions with surrounding biomolecules. Cross-linked lysozyme crystals of controlled size were functionalized with Pd(II) and reduced to Pd(0), operating as a size exclusion barrier for large macromolecules while enabling the traffic and chemical conversion of small molecule substrates with excellent efficiency, recyclability and tolerability. The capabilities of this catalytic system were harnessed ex vivo in salivary gland tissue to achieve epithelial progenitor cell differentiation by drug uncaging. This work provides a truly biocompatible strategy to extend catalytic processing and expands the scope of the field towards a new frontier: regenerative medicine. ^Cecilia Rocchi, Catherine Adam & Sara Illescas-Lopez are equal contributors.