Integrating PROTAC-based targeted protein degradation with nanodelivery systems to overcome cancer therapeutic resistance.

Tumor drug resistance is a major challenge in cancer treatment, as traditional chemotherapeutic agents and small molecule inhibitors often become ineffective in targeting tumors due to drug resistance. Proteolysis Targeting Chimeras (PROTAC) technology, as a novel protein degradation method, provides a new insight into overcoming drug resistance in tumors with the assistance of nanodelivery systems. PROTAC is able to degrade rather than merely inhibit tumor-associated proteins, thus avoiding drug resistance caused by gene mutations, protein overexpression and conformational changes, demonstrating significant advantages in overcoming tumor resistance. First, PROTAC eliminates the biological activity of the target protein by directly degrading it, thus overcoming the limitation of traditional inhibitors, which are susceptible to mutations of the structure and activity of the target protein. Second, PROTAC molecules are highly versatile and flexible, and can target proteins that are difficult to target with conventional drugs, including enzymatically inactive proteins, transcription factors and oncogenic protein complexes. In addition, PROTAC technology, with the booster of nanodelivery systems, can effectively improve solubility and bioavailability, enhance targeting and delivery efficiency while improving its stability, and can be combined with other therapeutic methods to further enhance the therapeutic effect. The versatility of PROTAC makes it a highly promising option for overcoming tumor drug resistance, and their effectiveness has been validated in a variety of cancers, including breast cancer, prostate cancer, and leukemia. In this paper, we will review the recent progress of PROTAC technology in overcoming tumor drug resistance and briefly summarize the advantages and challenges of PROTAC technology combined with nanodelivery system, hoping to provide valuable references for researchers in related fields.