From Small Molecules to Supramolecular Assemblies: The Paradigm Shift in Targeted Protein Degradation

Targeted protein degradation (TPD) offers a promising route to undruggable targets via the ubiquitin-proteasome pathway, but small-molecule PROTACs suffer from poor druggability, low tissue selectivity, and laborious linker optimization. Existing reviews cover individual nano-platforms separately; few have systematically compared the four core supramolecular degraders—SupTACs, hexamer-linker Nano-PROTACs, Split-and-Mix systems, and Nano-TACs. This review focuses on the paradigm shift from single small molecules to supramolecular assemblies, comparing design principles, fabrication routes, and therapeutic advantages across degradation pathways, substrate scope (proteins and RNA), and targeting modalities. It highlights the roles of non-covalent assembly, multivalent cooperativity, tissue-targeted delivery, pathway expansion, and modular reconfiguration in overcoming traditional bottlenecks, summarizes the technological evolution of self-assembled degradation systems, and analyzes current challenges including assembly heterogeneity, in vivo controllability, clinical translation, and safety, providing a technical and theoretical framework for next-generation precision-targeted, translatable degraders.