Rationally Designed Enzyme‐Resistant Peptidic Assemblies for Plasma Membrane Targeting in Cancer Treatment

• Published in: Advanced healthcare materials Vol. 12; no. 21; pp. e2301730 - n/a
• Main Authors: Zhang, Shijin, Gong, Xuewen, Wei, Qinchuan, Lv, Jiarong, Du, Enming, Wang, Jiaqing, Ji, Wei, Li, Ji‐Liang
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01-08-2023
• Subjects: Apoptosis; Assemblies; Cancer; Cancer therapies; Caspase; Cell death; Cytoskeleton; enzyme resistance; extrinsic apoptosis pathways; Hydrogen bonding; Hydrophobicity; Membranes; Multidrug resistance; Peptides; plasma membranes; Self-assembly; self‐assembling peptides; stress actin fibers; stress actin fibre; self-assembly peptide; extrinsic apoptosis pathway; plasma membrane; enzyme-resistance
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.202301730

Peptides are being increasingly important for subcellular targeted cancer treatment to improve specificity and reverse multidrug resistance. However, there has been yet any report on targeting plasma membrane (PM) through self‐assembling peptides. A simple synthetic peptidic molecule (tF4) is developed. It is revealed that tF4 is carboxyl esterase‐resistant and self‐assembles into vesical nanostructures. Importantly, tF4 assemblies interact with PM through orthogonal hydrogen bonding and hydrophobic interaction to regulate cancer cellular functions. Mechanistically, tF4 assemblies induce stress fiber formation, cytoskeleton reconstruction, and death receptor 4/5 (DR4/5) expression in cancer cells. DR4/5 triggers extrinsic caspase‐8 signaling cascade, resulting in cell death. The results provide a new strategy for developing enzyme‐resistant and PM‐targeting peptidic molecules against cancer.
An enzyme‐resistant peptidic molecule (tF4) is developed. Its assembling nanostructure interacts with HeLa cell plasma membrane, induces actin stress fibers formation, and results in cell death. Both in vitro and in vivo experiments demonstrate tF4's excellent tumoricidal activities and biocompatibility.