Lysosome-targeted protein degradation platforms for spatiotemporally controlled degradation.

Abstract

Lysosome-targeted protein degradation (LTPD) represents a therapeutic strategy that degrades membrane and extracellular target proteins through the endolysosomal pathway. LTPD chimeras are molecular degraders that mediate LTPD, but their in vivo performance is limited by poor spatiotemporal control of degradation-existing chimeras have suboptimal pharmacokinetics, tissue selectivity, and endolysosomal trafficking. To overcome these hurdles associated with chimeras, LTPD platforms have emerged. LTPD platforms function as chimera-loaded systems for targeted delivery and controlled release of chimeras, or as platform-based degraders that mediate disease-targeted and on-demand degradation without chimeras. We discuss how LTPD platforms spatiotemporally control degradation and describe their therapeutic applications. In particular, we summarize the design principles of LTPD platforms to address the stringent requirements imposed by the LTPD process. These principles may contribute to the rational design of LTPD platforms.