biostudies-literatureBi TScience and Technology Strategic Cooperation Project of Luzhou Municipal People's Government-Southwest Medical UniversityGuangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese MedicineSichuan Provincial Administration of Traditional Chinese Medicinean open project of the State Key Laboratory of Quality Research in Chinese Medicine funded by the Macau Science and Technology Development Fund (Macau University of Science and Technology, 006/2023/SKL), Macau Special Administrative Region.Sichuan Science and Technology Program192https://www.ebi.ac.uk/biostudies/studies/S-EPMC12933928biostudies-literatureUnknown24(1)Endothelial cells (ECs) of endothelial-to-mesenchymal transition (EndMT) are drivers of cardiac fibrosis. BRD4 has recently been identified as an epigenetic regulator of EndMT. Proteolysis-targeting chimera (PROTAC) technology has revolutionized targeted protein degradation, offering unprecedented opportunities for BRD4 modulation in diverse pathological contexts. Nevertheless, the non-selective cellular targeting profile of PROTACs poses significant limitations for their therapeutic application in cardiac fibrosis management. To address these limitations, we developed a GSH-responsive nanoscale PROTAC (RGD-PEG-MZ1) that targets activated platelets, leveraging their chemotactic properties to precisely degrade BRD4 in ECs. RGD-PEG-MZ1 exhibits selectivity for ECs and inhibition of EndMT, whJournal of nanobiotechnologyDesign of RGD-functionalized GSH-responsive pegylated polymeric protacs for selective BRD4 degradation and EndMT-driven cardiac fibrosis inhibition.PMC129339282023LSYS0022024NSFSC210125ZDIZX027Macau University of Science and Technology, 006/2023/SKL2024LZXNYDJ060Bi TChen LLi RYao XHuang RSu HZhai SLiu ZLuo PSun QHuang WWang TChen YMiao WZhou JfalseDesign of RGD-functionalized GSH-responsive pegylated polymeric protacs for selective BRD4 degradation and EndMT-driven cardiac fibrosis inhibition.Endothelial cells (ECs) of endothelial-to-mesenchymal transition (EndMT) are drivers of cardiac fibrosis. BRD4 has recently been identified as an epigenetic regulator of EndMT. Proteolysis-targeting chimera (PROTAC) technology has revolutionized targeted protein degradation, offering unprecedented opportunities for BRD4 modulation in diverse pathological contexts. Nevertheless, the non-selective cellular targeting profile of PROTACs poses significant limitations for their therapeutic application in cardiac fibrosis management. To address these limitations, we developed a GSH-responsive nanoscale PROTAC (RGD-PEG-MZ1) that targets activated platelets, leveraging their chemotactic properties to precisely degrade BRD4 in ECs. RGD-PEG-MZ1 exhibits selectivity for ECs and inhibition of EndMT, wh2026-01-01T00:00:00Z2026 Jan2026-07-16T20:49:14.395Z2026-07-10T03:13:41.781ZS-EPMC129339284161839310.1186/s12951-026-04036-7