Advances and challenges of targeted protein degradation in ophthalmology: Future directions and therapeutic potential

Abstract

The advent of targeted protein degradation technologies, particularly proteolysis-targeting chimeras (PROTACs) and lysosome-targeting chimeras (LYTACs), is poised to revolutionize therapeutic strategies in ophthalmology. This review presents the first systematic analysis of these protein degradation platforms to address ’undruggable’ targets in ocular pathologies. Harnessing distinct cellular machinery through the engagement of the ubiquitin–proteasome system and the lysosomal pathway with PROTACs and LYTACs, respectively, these heterobifunctional molecules enable the targeted elimination of disease-driving proteins implicated in ocular surface diseases, such as dry eye, and fundus diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. We review the mechanistic basis of these technologies, their translational potential in overcoming the limitations of conventional therapies, and ocular-specific challenges such as optimizing bioavailability and intraocular target selectivity. Central to this discussion is the role of advanced linker engineering in achieving spatio-temporal control of degradation activity. While barriers to ocular biodistribution and sustained delivery remain, targeted protein degradation represents a paradigm shift in ophthalmology, offering durable therapeutic effects that could significantly improve clinical outcomes and patient compliance through reduced dosing frequency.