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A strategy is developed for virion\u2010like membrane\u2010breaking nanoparticles (MBNs) to smoothly accomplish tumor\u2010activated cell\u2010and\u2010tissue dual\u2010penetration for surmounting impermeable drug\u2010resistant cancer. Tailor\u2010made dendritic arginine\u2010rich peptide prodrugs are designed to mimic viral protein transduction domains and globular protein architectures. Attractively, these protein mimics self\u2010assemble into virion\u2010like nanoparticles in aqueous solution, having highly ordered secondary structure. Tumor\u2010specific acidity conditions would activate the membrane\u2010breaking ability of these virion\u2010like nanoparticles to perforate artificial and natural membrane systems. As expected, MBNs achieve highly efficient drug penetration into drug\u2010resistant human ovarian (SKOV3\/R) cancer cells. Most importantly, the well\u2010organized MBNs can pass through endothelial\/tumor cells and spread from one cell to another one. Intravenous injection of MBNs into nude mice bearing impermeable SKOV3\/R tumors suggests that the MBNs can recognize the tumor tissue after prolonged blood circulation, evoke the membrane\u2010breaking function for robust transvascular extravasation, and penetrate into the deep tumor tissue. This work provides the first demonstration of sophisticated molecular and supramolecular engineering of virion\u2010like MBNs to realize the long\u2010awaited cell\u2010and\u2010tissue dual\u2010penetration, contributing to the development of a brand\u2010new avenue for dealing with incurable cancers.<\/jats:p>","DOI":"10.1002\/adma.201707240","type":"journal-article","created":{"date-parts":[[2018,5,18]],"date-time":"2018-05-18T02:18:19Z","timestamp":1526609899000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Virion\u2010Like Membrane\u2010Breaking Nanoparticles with Tumor\u2010Activated Cell\u2010and\u2010Tissue Dual\u2010Penetration Conquer Impermeable Cancer"],"prefix":"10.1002","volume":"30","author":[{"given":"Xiao","family":"Zhang","sequence":"first","affiliation":[{"name":"National Engineering Research Center for Biomaterials Sichuan University  Chengdu Sichuan 610064 P. R. 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