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Yet, the mechanisms remain elusive, which hinder the design of peptide\u2010based drugs. Here hendeca\u2010arginine peptides (R11) are synthesized for targeted delivery in bladder carcinoma (BC), investigated the targeting efficiency and elucidated the mechanism of peptide\u2010based delivery, with the aim of refining the design and efficacy of peptide\u2010based therapeutics. It is demonstrated that the over\u2010activated Piezo1\/integrin \u03b21 (ITGB1) signaling axis significantly facilitates tumor\u2010targeted delivery of R11 peptides via macropinocytosis. Furthermore, R11 peptides formed hydrogen bonds with integrin \u03b21, facilitating targeting and penetration into tumor cells. Additionally, R11 peptides protected integrin \u03b21 from lysosome degradation, promoting its recycling from cytoplasm to membrane. Moreover, this findings establish a positive feedback loop wherein R11 peptides activate Piezo1 by increasing membrane fusion, promoting Ca\n                    <jats:sup>2+<\/jats:sup>\n                    releasing and resulting in enhanced integrin \u03b21\u2010mediated endocytosis in both orthotopic models and clinical tissues, demonstrating effective tumor\u2010targeted delivery. Eventually, the Piezo1\/integrin \u03b21 signaling axis promoted cellular uptake and transport of peptides, establishing a positive feedback loop, promoting mechanical delivery to cancer and offering possibilities for drug modification in cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202409081","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T09:21:38Z","timestamp":1726046498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Enhanced Tumor\u2010Targeted Delivery of Arginine\u2010Rich Peptides via a Positive Feedback Loop Orchestrated by Piezo1\/integrin \u03b21 Signaling Axis"],"prefix":"10.1002","volume":"11","author":[{"given":"Minghai","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases Ministry of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases Ministry of Education  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases Ministry of Education  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tangdu Hospital Air Force Medical University  Xi'an 710038 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases Ministry of Education  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biomedical Information Engineering, Ministry of Education, Bioinspired Engineering and Biomechanics Center (BEBC), School of Life Science and Technology Xi'an Jiaotong University  Xi'an 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tangdu Hospital Air Force Medical University  Xi'an 710038 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