Targeted Protein Degradation: From Molecular Mechanisms to Emerging Therapeutic Strategies.
5 affiliations
- 1Department of Oncology The Affiliated Hospital of Yangzhou University, Yangzhou University Yangzhou Jiangsu China.
- 2Department of Pharmacy and Central Laboratory Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu Sichuan China.
- 3Department of Pathology School of Medicine, Duke University Durham North Carolina USA.
- 4Department of General Surgery The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery Hefei Anhui Province China.
- 5Jiangsu Provincial Innovation and Practice Base For Postdoctor Suining People's Hospital, Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China.
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.
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BibTeX
@article{guo2026targeted,
title = {{Targeted Protein Degradation: From Molecular Mechanisms to Emerging Therapeutic Strategies.}},
author = {Huaijuan Guo and Haishuang Duan and Yang Liu and Kelan Fang and Lujia Xiao and Ling Bai and Xiao Qu and Xuebing Yan and Kun Zhang},
journal = {MedComm},
year = {2026},
month = nov,
doi = {10.1002/mco2.71125},
url = {https://europepmc.org/article/MED/42996655},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeted Protein Degradation: From Molecular Mechanisms to Emerging Therapeutic Strategies.
AU - Huaijuan Guo
AU - Haishuang Duan
AU - Yang Liu
AU - Kelan Fang
AU - Lujia Xiao
AU - Ling Bai
AU - Xiao Qu
AU - Xuebing Yan
AU - Kun Zhang
PY - 2026
DA - 2026/11/05
JO - MedComm
DO - 10.1002/mco2.71125
UR - https://europepmc.org/article/MED/42996655
AB - 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.
SN - 2688-2663
ER -