The application of drug delivery systems based on targeted protein degradation chimeras in disease treatment strategies.

In recent years, the technology of targeted protein degradation (TPD) has developed rapidly. Proteolysis targeting chimeras (PROTACs) have achieved remarkable results in the specific clearance of target proteins through the ubiquitin-proteasome system. Meanwhile, novel strategies such as Molecular Glue, autophagosome tethering compounds (ATTEC), lysosome targeting chimeras (LYTAC) and autophagy targeting chimeras (AUTOTAC) have successively emerged. These approaches, through their distinct mechanisms, collectively expand the targeting dimensions of protein degradation. Unlike the occupancy-driven mechanism of traditional small-molecule inhibitors, TPD is event-driven. It can target "undruggable" proteins that are difficult to intervene with traditional small-molecule drugs. TPD can efficiently degrade target proteins at low doses, significantly reduce off-target toxicity and overcome drug resistance while enhancing the selectivity and specificity of drugs. However, most TPD face challenges such as poor solubility, low permeability, low bioavailability, poor tissue selectivity and the Hook effect, which prevent them from entering clinical trials in humans. Drug delivery systems (DDS) offer new insights into addressing these issues by improving the physicochemical properties of TPD, optimizing their pharmacokinetic characteristics and acting as transport carriers to increase tissue specificity, thereby enhancing the targeting of treatment. This review systematically summarizes the application progress of TPD technology in combination with DDS in neurodegenerative diseases, oncological diseases and vascular inflammatory diseases, and prospects for its future development.