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However, a water-soluble peptide called cell-penetrating peptide (CPP) has been known for its ability to directly penetrate through the biomembranes into cells (cytolysis) without perturbating cell viability and expected to be a promising drug delivery vector. Examples of CPP include peptides with multiple arginine units with strong cationic properties, which is the key to cytolysis. Here we show the conclusive evidence to support the mechanism of CPP\u2019s cytolysis and way to control it. The mechanism we proposed is attributed to biomembrane\u2019s physicochemical nature as lamellar liquid crystal (L\u03b1). Cytolysis occurs as the temporal and local dynamic phase transitions from L\u03b1 to an undulated lamellar with pores called Mesh<jats:sub>1<\/jats:sub>. We have shown this phase transfer of L\u03b1 composed of dioleoyl-phosphatidylcholine (DOPC) with water by adding oligo-arginine (Rx) as CPP at the equilibrium. Using giant unilamellar vesicle composed of DOPC as a single cell model, we could control the level of cytolysis of CPP (FITC-R8) by changing the curvature of the membrane through osmotic pressure modulation. The cytolysis of CPP utilizes biomembrane's inherent topological and functional flexibility corresponding to the stimuli.<\/jats:p>","DOI":"10.1038\/s41598-020-79518-1","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T11:13:01Z","timestamp":1610104381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Direct entry of cell-penetrating peptide can be controlled by maneuvering the membrane curvature"],"prefix":"10.1038","volume":"11","author":[{"given":"Kazutami","family":"Sakamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Morishita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Aburai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Imura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuhiko","family":"Nakase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiroh","family":"Futaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"79518_CR1","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1021\/acs.accounts.7b00221","volume":"50","author":"S Futaki","year":"2017","unstructured":"Futaki, S. & Nakase, I. 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