Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the Ubiquitin–Proteasome system

In eukaryotic cells, the ubiquitin–proteasome system (UPS) plays a crucial role in selectively breaking down specific proteins. The ability of the UPS to target proteins effectively and expedite their removal has significantly contributed to the evolution of UPS-based targeted protein degradation (TPD) strategies. In particular, proteolysis targeting chimeras (PROTACs) are an immensely promising tool due to their high efficiency, extensive target range, and negligible drug resistance. This breakthrough has overcome the limitations posed by traditionally "non-druggable" proteins. However, their high molecular weight and constrained solubility impede the delivery of PROTACs. Fortunately, the field of nanomedicine has experienced significant growth, enabling the delivery of PROTACs through nanoscale drug-delivery systems, which effectively improves the stability, solubility, drug distribution, tissue-specific accumulation, and stimulus-responsive release of PROTACs. This article reviews the mechanism of action attributed to PROTACs and their potential implications for clinical applications. Moreover, we present strategies involving nanoplatforms for the effective delivery of PROTACs and evaluate recent advances in targeting nanoplatforms to the UPS. Ultimately, an assessment is conducted to determine the feasibility of utilizing PROTACs and nanoplatforms for UPS-based TPD. The primary aim of this review is to provide innovative, reliable solutions to overcome the current challenges obstructing the effective use of PROTACs in the management of cancer, neurodegenerative diseases, and metabolic syndrome. Therefore, this is a promising technology for improving the treatment status of major diseases.