Bioorthogonal release-mediated targeted degradation of tripartite motif containing 24 protein for atherosclerosis...

Atherosclerosis is a progressive inflammatory disease in which macrophages play a central role in plaque formation and destabilization. Current anti-inflammatory drugs, such as statins and monoclonal antibodies, exhibit limited efficacy due to resistance, systemic immunosuppression, and their inability to target "undruggable" proteins. Proteolysis-targeting chimeras (PROTACs) provide an event-driven strategy for selective protein degradation, enabling sustained therapeutic effects and overcoming resistance. Tripartite Motif Containing 24 Protein (TRIM24), an E3 ubiquitin ligase involved in STAT6 acetylation and macrophage polarization, represents a promising therapeutic target; however, systemic degradation may cause off-target toxicity owing to broad tissue expression. Specifically, dTRIM24 is a PROTAC designed to specifically target and degrade the TRIM24 protein. To address this critical issue, we have developed a macrophage-specific bioorthogonally released degrader, BR-dTRIM24 (Bioorthogonally released dTRIM24), for the precise and controllable degradation of TRIM24. In this design, tetrazine-modified mannose (Man-Tz) selectively labeled macrophages and reacted with trans-cyclooctene-caged dTRIM24 (TCO-dTRIM24-TCO), ensuring localized release within plaque-associated macrophages. The released dTRIM24 triggered TRIM24 degradation, thereby reprogramming macrophages toward an anti-inflammatory state, reducing ox-LDL uptake, and promoting cholesterol efflux via the PPARγ-ABCA1 pathway. Consequently, plaque burden was alleviated in an atherosclerosis model. This study demonstrates that integrating bioorthogonal chemistry with PROTAC technology enables precise, efficient, and safe therapeutic modulation of atherosclerosis.