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Here, a poly(L\u2010glutamyl\u2010L\u2010lysine(EK) (p(EK))\u2010camouflaged, doxorubicin (Dox)\u2010conjugated nanomedicine is developed to demonstrate the underlying mechanism of zwitterionic shell in synchronous barrier\u2010penetration and biconditional active targeting. The zwitterionic p(EK) shell liquifies its surrounding water molecules in the polysaccharide gel of tumor\u00a0interstitium, leading to five times faster diffusion than the pegylated Doxil with similar size in tumor tissue. Its doped sulfonate groups lead to more precise active tumor\u2010targeting than disialoganglioside (GD2) antibody by meeting the dual requirements of tumor microenvironment (TME) pH and overexpression of GD2 on tumor. Consequently, the concentrations of the nanomedicine in tumor are always higher than in life\u2010supported organs in whole accumulation process, reaching over ten times higher Dox in GD2\u2010overexpressing MCF\u20107 tumors than in life\u2010supporting organs. Furthermore, the nanomedicine also avoids anti\u2010GD2\u2010like accumulation in GD2\u2010expressing kidney in a mouse model. Thus, the nanomedicine expands the therapeutic window of Doxil by more than three times and eliminates tumors with negligible myocardial and acute toxicity. This new insight paves an avenue to design nanodelivery systems for highly precise and safe chemotherapy.<\/jats:p>","DOI":"10.1002\/adma.202304594","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T14:08:45Z","timestamp":1693490925000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Integrating Liquification of the Gelated Tumor Interstitium around Nanomedicines with Biconditional GD2\u2010Targeting for Precise and Safe Chemotherapy"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8759-7449","authenticated-orcid":false,"given":"Weili","family":"Xue","sequence":"first","affiliation":[{"name":"Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang 310027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang 310027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangbo","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang 310027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Trital","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang 310027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang 310027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guping","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Zhejiang University  Hangzhou 310028 P. 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