LYTACs Review Maps Modular Design Principles and Diverse Therapeutic Applications for Extracellular Protein Degradation

Targeted protein degradation (TPD) offers a transformative therapeutic strategy, yet most existing approaches are limited to intracellular proteins, primarily utilizing the ubiquitin-proteasome system. This leaves a significant gap in addressing many disease-relevant extracellular and membrane-associated proteins. Lysosome-targeting chimeras (LYTACs) bridge this gap by harnessing the endosomal-lysosomal pathway, offering a novel mechanism to selectively degrade these previously undruggable targets. Understanding their design and mechanism is crucial for developing next-generation therapeutics.

This comprehensive review systematically examined the evolving landscape of LYTAC technology, focusing on its molecular architecture and mechanism of action. Researchers analyzed LYTACs from two key design perspectives: (1) the expanding diversity of protein-of-interest (POI) binders, including antibodies, aptamers, small molecules, peptides, and DNA scaffolds; and (2) the growing repertoire of lysosomal targeting receptors (LTRs), from classical receptors like cation-independent mannose-6-phosphate receptor (CI-M6PR) and asialoglycoprotein receptor (ASGPR) to emerging tissue-restricted and multifunctional entry routes. The review also discussed strategies to enhance degradation efficiency and improve pharmacokinetics/pharmacodynamics (PK/PD) profiles.

The review highlights the significant evolution of LYTAC design, demonstrating its modularity and adaptability. It detailed how various POI binders, including antibodies and peptides, can be effectively integrated into LYTAC constructs to target a broad range of extracellular and membrane proteins. A key finding is the expansion of LTRs beyond the well-established CI-M6PR and ASGPR, with new tissue-restricted and programmable receptors offering enhanced specificity and reduced off-target effects. This diversification allows for more precise targeting and broader therapeutic applicability. Strategies to enhance degradation efficiency include optimizing linker length and composition, while improving PK/PD profiles involves modifications to increase stability and bioavailability. The review also identified critical challenges for clinical translation, such as immunogenicity and delivery. > The systematic examination provides a robust framework for the rational design of next-generation LYTAC therapeutics, emphasizing the importance of optimizing both POI binding and lysosomal targeting for maximal efficacy.