Self‐Assembly of Therapeutic Peptide into Stimuli‐Responsive Clustered Nanohybrids for Cancer‐Targeted Therapy

• Published in: Advanced functional materials 2019-03, Vol.29 (10), p.n/a
• Main Authors: He, Wangxiao, Wang, Simeng, Yan, Jin, Qu, Yiping, Jin, Liang, Sui, Fang, Li, Yujun, You, Weiming, Yang, Guang, Yang, Qi, Ji, Meiju, Shao, Yongping, Ma, Peter X., Lu, Wuyuan, Hou, Peng
• Format: Article
• Language: English
• Subjects: Assembling; Batteries; Biocompatibility; Biomedical materials; Cancer; cancer targeted therapy; Copolymerization; Gold; immunotherapy; In vivo methods and tests; Materials science; Peptides; peptide‐derived nanocluster; peptide–Au nanohybrids; Proteins; Strategy; tumor microenvironment‐responsiveness; Tumors
• ISSN: 1616-301X; 1616-3028
• DOI: 10.1002/adfm.201807736

Clinical translation of therapeutic peptides, particularly those targeting intracellular protein–protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed β‐catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/β‐catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD‐L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide‐derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer. A strategy for clinical translation of therapeutic peptides by assembling them into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to the tumor microenvironment, is presented. An anticancer peptide termed β‐catenin/Bcl9 inhibitor is assembled into a cluster of nanohybrids termed pCluster, which potently inhibits tumor growth as well as metastasis, and synergizes with immunotherapy, while maintaining a highly favorable biosafety profile.