From simple delivery to multimodal systems: the critical role of macromolecular platforms in bioorthogonal drug synthesis

bond-forming synthesis mediated by transition metal catalysts, often enabled by the use of macromolecular platforms. By forming carbon-carbon or carbon-heteroatom bonds intra- or intermolecularly, this approach offers advantages over traditional uncaging strategies through the absence of the pharmacoactive motif in the prodrug. We emphasize the central role of macromolecular platforms in integrating bioorthogonal chemistries into multimodal systems that enable targeting strategies and stimuli-responsive behavior, both crucial for achieving site-specific activation and minimizing off-target effects. We conclude that the future of this field lies with the development of retrosynthetic prodrug design, and the use and development of multimodular macromolecular platforms to host and enable new bioorthogonal transition metal catalysis.