Multitargeted protein degradation: Integrating small-molecule, biomacromolecular, and nano-PROTACs for paradigm shifts in drug discovery

Proteolysis-targeting chimeras (PROTACs) have revolutionized drug discovery by enabling targeted protein degradation via the ubiquitin-proteasome system (UPS), overcoming limitations of traditional occupancy-based inhibitors. This innovative approach has expanded the therapeutic landscape, particularly for previously “undruggable” targets. Recent advances have led to the emergence of dual/multi-target PROTACs, which simultaneously degrade multiple disease-associated proteins, offering a novel strategy to tackle complex pathologies driven by interconnected molecular networks. Such multi-targeting is especially relevant in multifactorial diseases, including cancer and neurodegenerative disorders, where single-target inhibition often proves insufficient. This review comprehensively examines the latest advancements in dual-target/multi-target PROTACs, including small-molecule PROTACs, biomacromolecule PROTACs, and nano-PROTACs, with a particular focus on the design principles, mechanism insights, and therapeutic potential in various diseases. Furthermore, we critically evaluate existing challenges-such as selectivity, pharmacokinetic optimization, and resistance mechanisms-and discuss future perspectives to maximize their clinical impact in precision medicine.