Advancements in delivery Systems for Proteolysis-Targeting Chimeras (PROTACs): Overcoming challenges and expanding...

PROTAC (Proteolysis-Targeting Chimera), an emerging drug development strategy based on small molecule technology, has garnered widespread attention due to its high efficiency, broad applicability, low resistance, and dosage advantages. However, PROTAC molecules still exhibit certain limitations that require urgent resolution. Although significant progress has been made in designing PROTACs that target various disease-related proteins, research on drug delivery systems (DDS) for PROTACs remains relatively limited. This review aims to explore the critical role of delivery system design in addressing the inherent challenges associated with PROTAC molecules from a novel perspective. Beginning with five major challenges-insufficient targeting, poor pharmacokinetic properties, low cell permeability, limited accessibility, and the Hook effect-this article introduces formulation strategies to mitigate these deficiencies. It discusses potential solutions through targeted modifications, nano-delivery systems, intelligent response systems, and membrane biomimetic technologies, among others. Furthermore, it elucidates the mechanisms and principles underlying these approaches and analyzes the advantages of various delivery strategies. The insights provided in this review offer insights for designing delivery systems tailored to PROTACs with diverse characteristics for different disease applications.