Work

Targeted Protein Degradation: From Molecular Mechanisms to Emerging Therapeutic Strategies

Year: 2026

Type: review

Abstract: Targeted protein degradation (TPD) redirects endogenous protein clearance pathways to eliminate disease-associated proteins, offering an alternative to conventional occupancy-based inhibition. Advances in TPD have expanded the range of degradable targets from intracellular proteins to cell-surface and extracellular proteins, although these modalities differ in their mechanisms and delivery requirements. Translating these differences into rational degrader design and effective therapeutic strategies remains challenging. This review compares proteasome-dependent degradation, endocytosis-mediated lysosomal degradation, macroautophagy, and chaperone-mediated autophagy, together with representative degrader classes and target scope. We discuss molecular factors influencing degradation efficacy, including target accessibility, selection of degradation machinery, productive complex formation, degradation kinetics, and target resynthesis. We then examine strategies for improving degrader delivery and spatiotemporal control, including local administration, molecular conjugation, conditional activation, and nanotechnology. Particular attention is given to the roles of nanomaterials in improving degrader delivery, controlling drug release, and constructing functional nanoscale degradation systems. Finally, we summarize preclinical evidence and clinical advances in oncology and nononcology indications and discuss limitations and future directions for therapeutic translation. By integrating degradation mechanisms, molecular design, delivery strategies, and pharmacological considerations, this review provides a framework for selecting TPD approaches according to target biology and disease context.

Source: MedComm

DOI: 10.1002/mco2.71125