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Due to MMP upregulation in cancer microenvironments, matrix metalloproteinase (MMP)\u2010degradable linkers are often exploited for targeted release; however, their short substrates exhibit overlap with multiple proteases, which confounds kinetic control. Here, a library of MMP\u2010responsive \u201cpeptomer\u201d drug linkers was developed to control release on fast and slow timescales. Peptomers are hybrid molecules of peptides and non\u2010natural peptoids (N\u2010substituted glycines), which hinder proteolytic susceptibility. Systematic variation of peptoid substitutions within a pan\u2010MMP\u2010cleavable peptide sequence yielded distinct\u00a0degradation kinetics to multiple MMPs. Two chemotherapeutics, doxorubicin and geldanamycin, were conjugated to peptomer linkers and incorporated into polyethylene glycol (PEG)\u2010based hydrogels for sequential delivery. Fluorogenic and mass spectrometry\u2010based assays demonstrated decoupled release of each drug in response to MMP\u20102 and MMP\u20109. In vitro studies using MDA\u2010MB\u2010231 and A549 cells showed that cell death rates correlated with the order of drug release. These findings highlight peptomers as modular, biocompatible linkers capable of kinetic control over multiple therapeutic agents, providing a versatile platform for improving the precision of combination drug delivery systems.<\/jats:p>","DOI":"10.1002\/adhm.202504277","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T07:10:36Z","timestamp":1767165036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Peptomer Linkers Enable Kinetic Control over Co\u2010Delivery of Multiple Chemotherapeutics"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1780-9477","authenticated-orcid":false,"given":"Carolyn M.","family":"Watkins","sequence":"first","affiliation":[{"name":"McKetta Department of Chemical Engineering The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel L.","family":"Hallam","sequence":"additional","affiliation":[{"name":"McKetta Department of Chemical Engineering The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariah J.","family":"Austin","sequence":"additional","affiliation":[{"name":"McKetta Department of Chemical Engineering The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0207-7661","authenticated-orcid":false,"given":"Adrianne M.","family":"Rosales","sequence":"additional","affiliation":[{"name":"McKetta Department of Chemical Engineering The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001955\u20105"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16132478"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16723"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28261"},{"key":"e_1_2_8_6_1","author":"Blumenthal G.","year":"2021","journal-title":"Friends of Cancer Research White Paper"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crphar.2022.100110"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(23)00639\u20103"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549\u2010022\u201006755\u20105"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520\u2010015\u20102775\u20109"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.18553\/jmcp.2022.28.8.831"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.114724"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010023\u201000670\u20100"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2025.113782"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b07239"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2022.121721"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.8b17264"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.01.006"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matt.2022.03.001"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2022.09.014"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.5b01541"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202486099"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602884103"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4NA00086B"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medidd.2020.100024"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.03.015"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15010035"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885\u2010021\u201007860\u20102"},{"key":"e_1_2_8_29_1","first-page":"8221","article-title":"Expression of Matrix Metalloproteinases in the Microenvironment of Spontaneous and Experimental Melanoma Metastases Reflects the Requirements for Tumor Formation","volume":"63","author":"Hofmann U. 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