纳米医药在多糖凝胶填充的肿瘤间质中的快速扩散和精确主动靶向是尚未克服的两个主要障碍。在这里，我们开发了一种聚(L-谷氨酸-L-赖氨酸(EK))(p(EK))伪装、附加了阿霉素(Dox)的纳米医药，以展示带电离子外壳在同时穿过屏障和双重条件活性靶向中的潜在机制。带电离子的p(EK)外壳使肿瘤间质多糖凝胶周围的水分子液化，导致与肿瘤组织中与相似大小的聚乙二醇化Doxil®相比，扩散速度快了5倍。其掺杂的磺酸根团比二分脂肪酰神经酰胺二糖脂体(GD2)抗体更精确地靶向肿瘤，满足肿瘤微环境(pH值)和GD2在肿瘤中的过表达的双重要求。因此，在整个积累过程中，肿瘤中的纳米医药浓度始终高于生命支持器官，达到GD2过表达的MCF-7肿瘤中Doxol®的浓度是生命支持器官中的10倍以上。此外，纳米医药在小鼠模型中也避免了GD2表达的肾脏的抗-GD2类积累。因此，该纳米医药将Doxil®的治疗窗口扩大了3倍以上，并消除了肿瘤的心肌和急性毒性。这种新的认识为设计高精确性和安全性的纳米传递系统开辟了途径。本文受版权保护。版权所有。

The quick diffusion of nanomedicines in the polysaccharide-gel-filling tumor interstitium and precise active targeting are two major obstacles that have not yet been overcome. Here, we developed a poly(L-glutamyl-L-lysine(EK) (p(EK))-camouflaged, doxorubicin (Dox)-conjugated nanomedicine to demonstrate the underlying mechanism of zwitterionic shell in synchronous barrier-penetration and biconditional active targeting. The zwitterionic p(EK) shell liquifies its surrounding water molecules in the polysaccharide gel of tumor interstitium, leading to 5 times faster diffusion than the pegylated Doxil® with similar size in tumor tissue. Its doped sulfonate groups lead to more precise active tumor-targeting 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-supported organs in whole accumulation process, reaching over 10 times higher Dox in GD2-overexpressing MCF-7 tumors than in life-supporting organs. Furthermore, the nanomedicine also avoids anti-GD2-like accumulation in GD2-expressing kidney in a mouse model. Thus, the nanomedicine expands the therapeutic window of Doxil® by more than 3 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. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.