Nano-targeted protein degradation: Ushering in a new era of protein degradation therapeutics

Abstract

Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy that overcomes the limitations of conventional small-molecule inhibitors (SMIs) by harnessing the degradation machinery, including the ubiquitin-proteasome system (UPS) and lysosomal pathway. However, traditional TPD agents face substantial challenges in clinical translation, such as poor solubility, low bioavailability, insufficient targeting specificity, and limited tissue penetration. To address these limitations, the integration of nanotechnology has given rise to Nano-TPD as a new generation therapeutic platform that revolutionizes TPD delivery. We first summarize the recent advances in TPD technology for the treatment of common clinical diseases, highlighting key molecular targets and representative degraders. Then, we focus on the design of Nano-TPD platforms, including lipid-based, polymeric, inorganic, and biomimetic nanocarriers, as well as innovative strategies. The core mechanisms of Nano-TPD, encompassing targeted delivery, intracellular trafficking, stimuli-triggered release, and enhanced protein degradation via UPS or lysosomal pathways, are systematically elaborated. Furthermore, we discuss the challenges and future perspectives of Nano-TPD. This review provides a comprehensive overview of Nano-TPD, emphasizing its role in advancing TPD toward clinical utility and expanding its therapeutic scope across various diseases.