Recent advances in degraders engaging lysosomal pathways and related nanomedicine

The advent of targeted protein degradation (TPD) strategies presents unparalleled opportunities for innovating and expediting the development of new drugs. As the most mature TPD technology to date, proteolysis targeting chimeras (PROTACs) reliant on the ubiquitin proteasome system (UPS) have successfully transitioned from the laboratory to phase III clinical trials after nearly two decades of development. In recent years, the gradually emerging degraders engaging lysosomal pathways have further broadened the range of degradation mechanisms and substantially increased the diversity of potential targets and indications, ushering in a new era for the TPD field. Despite their significant advantages, the limited permeability, adverse pharmacokinetic properties, and off-target side effects caused by non-specific distribution still pose significant challenges to the clinical translation of these degraders. Currently, researchers are exploring the use of nanotechnology to surmount these obstacles and have achieved notable progress. This paper systematically summarizes the fundamental design principles, research status, challenges and future prospects of degraders engaging lysosomal pathways, and highlights the efforts and latest advances in related nanomedicine to optimize these degraders. The aim of this review is to deepen our comprehension of this emerging field and offer guidance for future exploration, development, and further utilization of new TPD techniques.