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However, their therapeutic efficacy is often compromised by the complex tumor microenvironment, which can lead to the reduced sensitivity of lung cancer cells to PROTACs. In this study, oxygen supplier (CaO2) and PROTAC co-loaded liposomes (LCP) are developed for simultaneously promoting EGFR degradation and hypoxic microenvironment alleviation. Calcium peroxide (CaO2) can release oxygen to modulate the hypoxic microenvironment, thereby reducing HIF-1\u03b1 expression and enhancing the sensitivity of lung cancer cells. Compared with PROTACs administered alone, LCP exhibited enhanced tumor cell killing effect, improved protein degradation capacity, and superior tumor growth inhibition in NSCLC animal models. Mechanistic analysis reveals that LCP modulates hypoxia-associated proteins, including FGFR1, ERK, and TGF-\u03b1, contributing to the enhanced therapeutic efficacy. The LCP developed herein offers a strategy for enhancing NSCLC therapy by remodeling the hypoxic tumor microenvironment.<\/jats:p>","DOI":"10.1021\/acsami.6c10600","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:07:34Z","timestamp":1789535254000},"page":"47402-47422","source":"Crossref","is-referenced-by-count":0,"title":["EGFR-Degrading PROTACs and Calcium Peroxide Co-loaded Liposomes: Enabling EGFR Degradation and Hypoxia Alleviation as Dual Safeguards for NSCLC Therapy"],"prefix":"10.1021","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4775-3331","authenticated-orcid":true,"given":"Lei","family":"Fang","sequence":"first","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wu","sequence":"additional","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarui","family":"Wang","sequence":"additional","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6031-3862","authenticated-orcid":true,"given":"Yu","family":"Wu","sequence":"additional","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4945-9492","authenticated-orcid":true,"given":"Junhui","family":"Ma","sequence":"additional","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuju","family":"Li","sequence":"additional","affiliation":[{"name":"Tongren Polytechnic College , , ,","place":["Tongren, China, 554300"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Deng","sequence":"additional","affiliation":[{"name":"Tongren Polytechnic College , , ,","place":["Tongren, China, 554300"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Ma","sequence":"additional","affiliation":[{"name":"Tongren Polytechnic College , , ,","place":["Tongren, China, 554300"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Li","sequence":"additional","affiliation":[{"name":"Tongren Polytechnic College , , ,","place":["Tongren, China, 554300"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangya","family":"Xiang","sequence":"additional","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]},{"name":"Tongren Polytechnic College , , ,","place":["Tongren, China, 554300"]},{"name":"Institute of The Higher Education Edible and Medicinal Fungi Engineering Research Center , ,","place":["Tongren, China, 554300"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4954-9251","authenticated-orcid":true,"given":"Xiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Tongji Medical College, Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]},{"name":"Tongren Polytechnic College , , ,","place":["Tongren, China, 554300"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"3","key":"2026091612073525200_cit1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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