Nanotechnology-Enabled Targeted Protein Degradation for Cancer Therapeutics.

Targeted protein degradation (TPD) represents an innovative therapeutic strategy that has garnered considerable attention from both academic and industrial sectors due to its promising developmental prospects. Approximately 85% of human proteins are implicated in disease pathogenesis, and the FDA has approved around 400 drugs targeting these disease-related proteins, predominantly enzymes, transcription factors, and non-enzymatic proteins. However, existing therapeutic modalities fail to address certain "high-value" targets, such as c-Myc and Ras. The emergence of proteolysis-targeting chimeras (PROTAC) technology has introduced TPD into a new realm. The capability to target non-druggable sites has expanded the therapeutic horizon of protein-based drugs, although challenges related to bioavailability, safety, and adverse side effects have constrained their clinical progression. Nano-delivery systems and emerging TPD modalities, such as molecular glues, lysosome-targeted chimeras (LYTACs), autophagy system compounds (ATTEC), and antibody PROTAC (AbTACs), have mitigated some of these limitations. This paper reviews the latest advancements in TPD, highlighting their applications and benefits in cancer therapy, and concludes with a forward-looking perspective on the future development of this field.