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Proteolysis targeting chimeras (PROTACs) have been utilized to overcome drug resistance by degrading mutant EGFR, but most are restricted to their poor cell permeability and insufficient tumor\u2010targeting ability. Meanwhile, these PROTACs has little effect on bypass resistance mechanisms. In this study, a versatile split\u2010and\u2010mix liposomal PROTAC is developed for EGFR degradation based on liposome self\u2010assembly containing DSPE\u2010PEG2000\u2010E3 ligand and DSPE\u2010PEG2000\u2010EGFR ligand. Unlike traditional PROTACs, this platform can achieve efficient EGFR degradation via both E3\u2010dependent mechanisms and the lysosome\u2010autophagy pathway. To further increase its sensitivity to osimertinib\u2010resistant lung cancer cells, the liposomal PROTAC is encapsulated with class I HDAC inhibitor MS\u2010275 (GM\u2010protac) by both blocking the EGFR\u2010dependent pathways and bypass resistant mechanisms. GM\u2010protac shows selective toxicity on gefitinib\u2010resistant and osimertinib\u2010resistant lung cancer cells. The mechanism analysis reveals that GM\u2010protac can influence the BIM\u2010associated apoptosis pathway, c\u2010Met, PD\u2010L1, HER\u20102, NF\u2010\u03baB or PI3K\u2010AKT signaling pathway, etc. Meanwhile, they displayed obvious tumor inhibition with negligible toxicity in both osimertinib and gefitinib\u2010resistant lung cancer animal models. This work provides an alternative option for osimertinib\u2010resistant lung cancer therapy.<\/jats:p>","DOI":"10.1002\/advs.202510197","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T04:13:36Z","timestamp":1755836016000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["EGFR Targeted Liposomal PROTAC Assisted With Epigenetic Regulation as an Efficient Strategy for Osimertinib\u2010Resistant Lung Cancer Therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Dongyuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"},{"name":"Hubei Province Clinical Research Center for Precision Medicine for Critical Illness  Wuhan 430022 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