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Migrating cancer stem cells (miCSCs), marked by CD133\u207aCXCR4\u207a expression is a key driver of PDAC progression, which currently lack effective therapeutic targets. Activated pancreatic stellate cells (PSCs) within the tumor microenvironment secrete CXCL12, the ligand for CXCR4, thereby promoting stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance in miCSCs. Despite advances in understanding PDAC biology, clinically effective strategies that target CXCR4\u207a CSC populations remain limited. In order to investigate the molecular mechanisms sustaining miCSCs, we performed protein\u2013protein interaction network analysis, which identified the transcription factor BMI1 as a key downstream effector of the CXCL12\/CXCR4 axis. Functional studies using shRNA-mediated knockdown of CXCR4 and BMI1 were conducted to assess their roles in miCSC migration, EMT, and self-renewal. We further evaluated the therapeutic potential of the endogenous CXCR4 antagonist EPI-X4 and its optimized derivative JM#21 in PDAC cell lines. We addressed the peptide stability by encapsulating JM#21 into mesoporous silica nanoparticles (MSNs) designed for improved half-life and sustained release under physiological conditions. BMI1 was confirmed as a critical mediator of CXCL12\/CXCR4-driven stemness and EMT. Knockdown of CXCR4 or BMI1 significantly impaired miCSC maintenance and migration towards CXCL12. Both EPI-X4 and JM#21 potently inhibited CXCL12-mediated signaling, reduced EMT and stemness markers, and suppressed miCSC migratory potential. JM#21 displayed superior efficacy and re-sensitized previously resistant PDAC cell lines to gemcitabine and paclitaxel. Functional assays demonstrated that nanoparticle-loaded JM#21 more effectively suppressed EMT markers and self-renewal than the free peptide, highlighting the advantage of nanoparticle delivery in therapeutic applications. Given their biocompatibility and modularity, silica nanoparticles offer a promising platform for stabilizing peptide drugs. Our findings reveal that tumor\u2013stroma crosstalk via the CXCL12\/CXCR4\/BMI1 axis plays a central role in sustaining miCSC-driven metastasis and therapy resistance in PDAC. Targeting this signaling pathway with nanoparticle-stabilized JM#21 represents a novel and clinically promising therapeutic strategy to disrupt PDAC progression and improve the efficacy of existing combination treatments.<\/jats:p>","DOI":"10.1038\/s41598-026-48584-2","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T16:07:26Z","timestamp":1776355646000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A CXCR4 targeting peptide delivered by silica nanoparticles eliminates migrating cancer stem cells in pancreatic ductal adenocarcinoma"],"prefix":"10.1038","volume":"16","author":[{"given":"Kanishka","family":"Tiwary","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton","family":"Lahusen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syeda","family":"Inaas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastian","family":"Beitzinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirja","family":"Harms","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Hauff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolin","family":"Walter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Alcala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"He\u00dfmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Kleger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ninel","family":"Azoitei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Bruno","family":"Sainz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"M\u00fcnch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Lind\u00e9n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick C.","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"48584_CR1","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","volume":"74","author":"L Rahib","year":"2014","unstructured":"Rahib, L. et al. 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All other Authors have no competing interests to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The patient derived xenograft used in this study were obtained under the Material Transfer Agreement with Spanish National Cancer Center (CNIO), Madrid, Spain (Reference no. I409181220BSMH and I405271505PHMH) followed by the ethics committee approval of Ulm University (161\/15 \u2013 The role of circulating cancer stem cells in EMT and Metastasis). The patient derived organoids were obtained by the biobank of the University Hospital of Ulm followed by the ethics committee approval of Ulm University (72\/2019: PDAC Liver Metastasis) and (67\/2019: human tissue and blood).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"12588"}}