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However, cost, lability, disorderly sequences, systemic toxicology, and biological profiles have plagued the perennial search. Here, a progressive \u03b2\u2010hairpin solution with the simplest formulation is implanted into an AMP\u2010based therapeutic strategy to systematically reveal the complex balance between function and toxicity of structural moieties, including cationicity, hydrophobicity, cross\u2010strand interactions, center bending, and sequence pattern. Comprehensive implementation of structural identification, ten microorganisms, eleven in vitro barriers, four mammalian cells, and a diversified membrane operation setup led to the emergence of \u03b2\u2010hairpin prototypes from a 24\u2010member library. Lead amphiphiles, WKF\u2010PG and WRF\u2010NG, can tackle bacterial infection through direct antimicrobial efficacy and potential inflammation\u2010limiting capabilities, such as an <jats:italic>Escherichia coli<\/jats:italic> challenge in a mouse peritonitis\u2010sepsis model, without observed toxicity after systemic administration. Their optimal states with dissimilar modulators and the unavailable drug resistance related to membrane lytic mechanisms, also provide an usher for renewed innovation among \u03b2\u2010sheet peptide\u2010based antimicrobial biomaterials.<\/jats:p>","DOI":"10.1002\/smll.202003899","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T12:51:58Z","timestamp":1608814318000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Cross\u2010Strand Interaction, Central Bending, and Sequence Pattern Act as Biomodulators of Simplified \u03b2\u2010Hairpin Antimicrobial Amphiphiles"],"prefix":"10.1002","volume":"17","author":[{"given":"Changxuan","family":"Shao","sequence":"first","affiliation":[{"name":"Institute of Animal Nutrition Northeast Agricultural University  Harbin 150030 P. R. 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