Aqueous Self-Assembly of Block Copolymers to Form Manganese Oxide-Based Polymeric Vesicles for Tumor Microenvironment-Activated Drug Delivery

HIGHLIGHTS: The formation of manganese oxide induces self-assembly of block copolymers to form polymeric vesicles. The polymeric vesicles possessed strong stability and high drug loading capacity. The drug-loaded polymeric vesicles have been demonstrated, especially in in vivo studies, to exhibit a higher efficacy of tumor suppression without known cardiotoxicity. ABSTRACT: Molecular self-assembly is crucially fundamental to nature. However, the aqueous self-assembly of polymers is still a challenge. To achieve self-assembly of block copolymers [(polyacrylic acid–block–polyethylene glycol–block–polyacrylic acid (PAA(68)–b–PEG(86)–b–PAA(68))] in an aqueous phase, manganese oxide (MnO(2)) is first generated to drive phase separation of the PAA block to form the PAA(68)–b–PEG(86)–b–PAA(68)/MnO(2) polymeric assembly that exhibits a stable structure in a physiological medium. The polymeric assembly exhibits vesicular morphology with a diameter of approximately 30 nm and high doxorubicin (DOX) loading capacity of approximately 94%. The transformation from MnO(2) to Mn(2+) caused by endogenous glutathione (GSH) facilitates the disassembly of PAA(68)–b–PEG(86)–b–PAA(68)/MnO(2) to enable its drug delivery at the tumor sites. The toxicity of DOX-loaded PAA(68)–b–PEG(86)–b–PAA(68)/MnO(2) to tumor cells has been verified in vitro and in vivo. Notably, drug-loaded polymeric vesicles have been demonstrated, especially in in vivo studies, to overcome the cardiotoxicity of DOX. We expect this work to encourage the potential application of polymer self-assembly. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40820-020-00447-9) contains supplementary material, which is available to authorized users.