biostudies-literatureXing HConsejo Nacional de Investigaciones Científicas y TécnicasUS-Egypt Joint Board on Scientific and Technological Cooperation (U.S. - Egypt Joint Board)US-Egypt Joint Board on Scientific and Technological CooperationNational Science Foundation (NSF)Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)National Science Foundatione2321498121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11032466biostudies-literatureUnknown121(16)In recent decades, peptide amphiphiles (PAs) have established themselves as promising self-assembling bioinspired materials in a wide range of medical fields. Herein, we report a dual-therapeutic system constituted by an antimicrobial PA and a cylindrical protease inhibitor (LJC) to achieve broad antimicrobial spectrum and to enhance therapeutic efficacy. We studied two strategies: PA-LJC nanostructures (<i>Encapsulation</i>) and PA nanostructures + free LJC (<i>Combination</i>). Computational modeling using a molecular theory for amphiphile self-assembly captures and explains the morphology of PA-LJC nanostructures and the location of encapsulated LJC in agreement with transmission electron microscopy and two-dimensional (2D) NMR observations. The morphology and release profile of PA-LJC Proceedings of the National Academy of Sciences of the United States of AmericaEngineering a nanoantibiotic system displaying dual mechanism of action.PMC11032466ANPCyT PICT 1520-201972026321CA00001DMR-1941731Conda-Sheridan Mde Campos LJXing HPereira AJFiora MMTagliazucchi MAguiar-Alves FfalseEngineering a nanoantibiotic system displaying dual mechanism of action.In recent decades, peptide amphiphiles (PAs) have established themselves as promising self-assembling bioinspired materials in a wide range of medical fields. Herein, we report a dual-therapeutic system constituted by an antimicrobial PA and a cylindrical protease inhibitor (LJC) to achieve broad antimicrobial spectrum and to enhance therapeutic efficacy. We studied two strategies: PA-LJC nanostructures (<i>Encapsulation</i>) and PA nanostructures + free LJC (<i>Combination</i>). Computational modeling using a molecular theory for amphiphile self-assembly captures and explains the morphology of PA-LJC nanostructures and the location of encapsulated LJC in agreement with transmission electron microscopy and two-dimensional (2D) NMR observations. The morphology and release profile of PA-LJC 2024-01-01T00:00:00Z2024 Apr2025-04-18T19:43:59.875Z2025-04-07T07:29:51.483ZS-EPMC110324663859307710.1073/pnas.2321498121