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To address this need, we developed a pillar\u2013perfusion 3D breast cancer spheroid platform to screen a six\u2010peptide panel\u2014P1 (Fmoc\u2010FF\u2010pTyr), P2 (Fmoc\u2010FF\u2010pThr), P3 (RGD\u2010FF\u2010pTyr), P4 (NBD\u2010FF\u2010pTyr), P5 (Nap\u2010FF\u2010pTyr), and P6 (Nap\u2010FF\u2010pThr)\u2014under static and dynamic flow. Hydrogel optimization identified a 2% gelatin\/1% alginate matrix enabling\n                    <jats:italic>&gt;<\/jats:italic>\n                    90% spheroid transfer efficiency and stable non\u2010invasive morphology, while Matrigel\u2010based embedding generated invasive spheroids mimicking metastatic behavior. Across the peptide panel, P1 and P5 produced the strongest cytotoxic effects, with dynamic perfusion further enhancing activity (P1 viability\n                    <jats:italic>\u223c<\/jats:italic>\n                    55% at 100\u2009\u03bcM). Co\u2010treatment with P1\u2009+\u20095\u2009\u03bcM Doxorubicin resulted in enhanced viability loss and complete inhibition of invasion. Fluorescence imaging of NBD\u2010FF\u2010pTyr confirmed progressive intratumoral penetration and core accumulation over 5\u2009days. RT\u2010qPCR analysis demonstrated peptide\u2010 and subtype\u2010specific transcriptional effects, with P1 in MCF\u20107 spheroids significantly downregulating\n                    <jats:italic>BCL2<\/jats:italic>\n                    ,\n                    <jats:italic>BRCA2<\/jats:italic>\n                    , and\n                    <jats:italic>TP53<\/jats:italic>\n                    , while P5 in MDA\u2010MB\u2010231 spheroids produced the strongest repression of survival and DNA\u2010repair pathways. These findings establish a dynamic, high\u2010throughput 3D platform for comparative EISAP screening and demonstrate the therapeutic potential of enzyme\u2010responsive peptides in complex tumor microenvironments.\n                  <\/jats:p>","DOI":"10.1002\/btm2.70135","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:40:26Z","timestamp":1775752826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic pillar\u2013perfusion platform for screening enzyme\u2010induced self\u2010assembling peptide therapeutics in\n                    <scp>3D<\/scp>\n                    breast cancer spheroids"],"prefix":"10.1002","volume":"11","author":[{"given":"Andrea","family":"Escobar Martinez","sequence":"first","affiliation":[{"name":"Biomedical Engineering Department University of North Texas  Denton Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranav","family":"Joshi","sequence":"additional","affiliation":[{"name":"Bioprinting Laboratories Inc.  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