Lysosome-targeting degrader delivery system: from formulation design to biomedical applications

Lysosome-targeting degraders (LYTADs) are bifunctional molecules that harness lysosomes to degrade pathogenic proteins. This breakthrough technology addresses a gap in cell membrane- and extracellular protein-targeted degradation technologies. Together with proteolysis-targeting chimeras, LYTADs have driven the development and application of targeted protein degradation (TPD) in biomedicine and other fields, making it one of the most prominent chemical biology technologies of the 21st century. Currently, LYTAD technology has been extensively researched and expanded, demonstrating its ability to degrade a variety of pathogenic proteins across cells, tissues, and diseases, and is not limited to TPD. LYTADs are now in the critical stage of translating their concepts into clinically validated drugs. Many emerging limitations and challenges cannot be addressed through structural design and optimization alone. With the increasing demand for accelerated clinical translation, delivery systems are being used to improve the physicochemical properties of LYTAD molecules in both in vivo and in vitro settings. By combining delivery system design strategies with LYTAD design, or by harnessing delivery systems to deliver LYTADs, the targeting capabilities, therapeutic effects, and biosafety of LYTADs can be enhanced. This integration of delivery systems and LYTADs brings new breakthroughs and opportunities to the field of TPD. In this review, we summarize recent advances in LYTAD delivery systems, focusing on design strategies and biomedical applications. We will also discuss the current challenges and envision future development opportunities of this technology in the biomedical field.