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Hypoxia, acidosis, and elevated interstitial fluid pressure limit drug penetration, while cancer-associated fibroblasts and immunosuppressive cells promote survival signaling, drug efflux, and metabolic adaptation. Polymeric drug delivery systems offer a promising strategy to address these barriers because their structures can be precisely engineered and designed to respond to TME-specific stimuli. These properties enable controlled drug release at tumor sites and help improve therapeutic efficacy while reducing systemic limitations. This review discusses how physicochemical and cellular components of the TME contribute to drug resistance and how polymeric nanomedicines can be designed to overcome these barriers. In addition, it examines key challenges that limit clinical translation, including tumor heterogeneity, variable enhanced permeability and retention effects, manufacturing scalability, and regulatory requirements. Finally, this review highlights the future direction of polymer nanomedicine and focuses specifically on developing rational material design, enhancing preclinical models, and developing clinically appropriate strategies to combat TME-mediated drug resistance.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060674","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:58:38Z","timestamp":1780473518000},"page":"674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Polymeric Nano Drug Delivery Systems for Overcoming Tumor Microenvironment-Mediated Drug Resistance"],"prefix":"10.3390","volume":"18","author":[{"given":"Yonggyu","family":"Kang","sequence":"first","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Department of Smart Health Science and Technology, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jisu","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Department of Smart Health Science and Technology, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subin","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Department of Smart Health Science and Technology, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngjin","family":"An","sequence":"additional","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7341-8788","authenticated-orcid":false,"given":"Kwang Suk","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Department of Smart Health Science and Technology, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Institute of Fermentation of Brewing, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8161-683X","authenticated-orcid":false,"given":"Hyun-Ouk","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Chemical Engineering and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Department of Smart Health Science and Technology, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"},{"name":"Institute of Fermentation of Brewing, Kangwon National University, Chuncheon-si 24341, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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