Supramolecular Degraders: An Emerging Paradigm in Targeted Protein Degradation.

Targeted protein degradation (TPD) redirects endogenous protein-disposal pathways to selectively eliminate therapeutically relevant proteins. Over the past two decades, this field has progressed from proteolysis-targeting chimeras (PROTACs) to an expanding repertoire of proteasomal and lysosomal degradation strategies. Recent studies indicate that supramolecular strategies are emerging in TPD, with dynamic noncovalent interactions and ordered assembly shaping degrader construction, delivery, functional integration, or intracellular assembly or activation. Here we organize recent advances into four major modes of supramolecular involvement, encompassing noncovalent modular decoupling of degrader components, delivery-oriented single-component self-assembly, multicomponent co-assembly for functional integration, and intracellular in situ assembly that generates either persistent local architectures or active degraders following cellular entry. We discuss their applications across proteasomal, endosomal-lysosomal, and autophagy-lysosomal degradation pathways. Finally, we discuss translational challenges and emerging opportunities for advancing supramolecular degraders, spanning modular design, strategy diversification, indication selection, systemic biodistribution, intracellular trafficking, safety assessment, and the prospective use of artificial intelligence (AI)-assisted modeling.