biostudies-literatureWang NStarr Cancer ConsortiumMr. William H and Mrs. Alice GoodwinDoris Duke Charitable FoundationCommonwealth Foundation for Cancer Research FoundationCommonwealth Foundation for Cancer Research the Center for Experimental TherapeuticsNational Cancer InstituteNCI NIH HHS2067-2077https://www.ebi.ac.uk/biostudies/studies/S-EPMC11770985biostudies-literatureUnknown23(6)Engineered macromolecules offer compelling means for the therapy of conventionally undruggable interactions in human disease. However, their efficacy is limited by barriers to tissue and intracellular delivery. Inspired by recent advances in molecular barcoding and evolution, we developed BarcodeBabel, a generalized method for the design of libraries of peptide barcodes suitable for high-throughput mass spectrometry proteomics. Combined with PeptideBabel, a Monte Carlo sampling algorithm for the design of peptides with evolvable physicochemical properties and sequence complexity, we developed a barcoded library of cell penetrating peptides (CPPs) with distinct physicochemical features. Using quantitative targeted mass spectrometry, we identified CPPS with improved nuclear and cytoplasmic dJournal of proteome researchProteomic Barcoding Platform for Macromolecular Screening and Delivery.PMC11770985R01 CA204396R21 CA235285U54 CA243124P30 CA008748R01 CA214812P30 CA08748Wang NFass JEton EKentsis AMcneer NAfalseProteomic Barcoding Platform for Macromolecular Screening and Delivery.Engineered macromolecules offer compelling means for the therapy of conventionally undruggable interactions in human disease. However, their efficacy is limited by barriers to tissue and intracellular delivery. Inspired by recent advances in molecular barcoding and evolution, we developed BarcodeBabel, a generalized method for the design of libraries of peptide barcodes suitable for high-throughput mass spectrometry proteomics. Combined with PeptideBabel, a Monte Carlo sampling algorithm for the design of peptides with evolvable physicochemical properties and sequence complexity, we developed a barcoded library of cell penetrating peptides (CPPs) with distinct physicochemical features. Using quantitative targeted mass spectrometry, we identified CPPS with improved nuclear and cytoplasmic d2024-01-01T00:00:00Z2024 Jun2025-04-04T22:23:28.205Z2025-04-04T22:23:28.205ZS-EPMC117709853877643010.1021/acs.jproteome.4c00068