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Hierarchical self-assembly of synthetic polypeptides has attracted increasing interests due to its protein-mimetic structure and great potential in nanotechnology and biomedical applications. However, controlling the morphology and function of polymeric nanostructures via secondary structures remains largely unexplored. Here, we report an unusual micelle-to-vesicle transformation of cholesterol-decorated poly(l-cysteine) copolymer assemblies in response to reactive oxygen species (ROS). We found that the interesting morphological transition correlates with the alteration in conformations from β-sheet to α-helix, which grants an attractive "on-off" switch for triggered release and cellular interaction. We further demonstrated the usefulness of the conformation-regulated assembly strategy both in vitro and in vivo, taking cancer treatment as a model. The work offers a new insight on the folding and hierarchical assembly of polypeptides and a novel approach for the development of smart platforms in biosensing, disease treatment, and diagnostic applications.

Although anti‐angiogenic therapies (AATs) have some effects against multiple malignancies, they are limited by subsequent tumor vasculogenesis and progression. To investigate the mechanisms by which tumor vasculogenesis and progression following AATs, we transfected microRNA (miR)‐9 into human umbilical vein endothelial cells (HUVECs) to mimic the tumor‐associated endothelial cells in hepatocellular carcinoma and simulated the AATs in vitro and in vivo. We found that administration of the angiogenesis inhibitor vandetanib completely abolished miR‐9‐induced angiogenesis and promoted autophagy in HUVECs, but induced the release of vascular endothelial growth factor (VEGF)‐enriched exosomes. These VEGF‐enriched exosomes significantly promoted the formation of endothelial vessels and vasculogenic mimicry in hepatocellular carcinoma and its progression in mice. Anti‐autophagic therapy is proposed to improve the efficacy of AATs. However, similar effects by AATs were observed with the application of anti‐autophagy by 3‐methyladenine. Our results revealed that tumor vasculogenesis and progression after AATs and anti‐autophagic therapies were due to the cross‐talk between endothelial cells and tumor cells via VEGF‐enriched exosomes. These findings provide a critical insight into a new interpretation of why AATs have not achieved expected outcomes. They also suggest that control of exosome release or alteration of exosome cargo composition to inhibit tumor vasculogenesis may augment the anti‐angiogenic and anti‐autophagic therapies for tumors. Support or Funding Information Supported by National Natural Science Foundation of China (Grant no.11402153). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Specific accumulation of therapeutics at tumor sites to improve in vivo biodistribution and therapeutic efficacy of anticancer drugs is a major challenge for cancer therapy. Herein, we demonstrate a new generation of intelligent nanosystem integrating multiple functionalities in a single carrier based on multifunctional multiblock polyurethane (MMPU). The smart nanocarriers equipped with stealth, active targeting, and internalizable properties can ferry paclitaxel selectively into tumor tissue, rapidly enter cancer cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in an improved biodistribution and excellent antitumor activity in vivo. Our work provides a facile and versatile approach for the design and fabrication of smart intracellular targeted nanovehicles for effective cancer treatment, and opens a new era in the development of biodegradable polyurethanes for next-generation nanodelivery systems.