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Stealth coating materials effectively extend a nanoparticle's systemic circulation lifetime yet limit its cellular internalization, which promotes and prevents tumor targeting, respectively. Here, this contradiction was resolved by using an acutely pH-sensitive zwitterionic stealth ligand capable of responding to small differences in extracellular pH between blood and tumors. Using a photothermal gold nanocage (AuNC) as a model nanotherapeutic, we found that stealth-AuNC nanoparticles showed both significantly enhanced cell uptake efficiency in acidic tumors and a markedly extended systemic circulation lifetime compared to its unaltered analogue. As a result, stealth-AuNC nanoparticles administered intravenously showed significantly enhanced accumulation within the tumor, leading to significantly improved photothermal therapeutic efficacy in mouse models. These results suggests that pH-sensitive zwitterionic ligands with sufficient sensitivity for responding to small differences in extracellular pH between blood and tumors are ideal stealth materials for simultaneously conferring both extended systemic circulation and enhanced cellular internalization, reducing the need for active targeting moieties.
We gratefully thank Professors Jun Wang and Zhishen Ge for use of their facilities. This work was supported in part by the National Natural Science Foundation of China (Nos. 21174138 and 31671014, L. Y.; 21474097, Y. Z. Y.), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (No. 2014293, L. Y.), the Recruitment Program of Global Experts and the Hundred Talent Program of the Chinese Academy of Sciences (Y. J. X.), and the National Natural Science Funds for Distinguished Young Scholar (No. 51625305, Y. Z. Y.).