Targeted degrader conjugates (TDCs): Modalities for precision delivery of PROTACs and molecular glue degraders

Proteolysis targeting chimeras (PROTACs) and molecular glue degraders (MGDs) have revolutionized drug discovery by exploiting the intracellular ubiquitin–proteasome system (UPS) to induce selective degradation of pathogenic proteins. However, their clinical development is frequently constrained by poor drug-like properties, limited cell permeability, unfavorable pharmacokinetics, and systemic off-target toxicities. To overcome these limitations, targeted degrader conjugates (TDCs)—innovative platforms that covalently tether PROTACs or MGDs to disease-targeting moieties via specialized linkers—have emerged as a promising tissue-restricted delivery modality for degraders. According to the different targeting moieties, TDCs are classified as degrader‒antibody conjugates (DACs), degrader‒peptide conjugates (DPCs), degrader‒aptamer conjugates (DApCs), degrader‒small molecule conjugates (DSMCs), and degrader‒protein conjugates (DProCs). Beyond summarizing recent advances, this review introduces a seven-step delivery cascade model as an organizing tool for understanding the intracellular fate of TDCs. This framework facilitates a systematic comparison of distinct TDC platforms and helps identify critical factors in delivery and degradation efficiency. We further highlight the key biological bottlenecks, translational hurdles, and emerging engineering strategies that may support the further development of targeted protein degradation therapies.