{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T09:05:36Z","timestamp":1780995936668,"version":"3.54.1"},"reference-count":73,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH New Innovator Award","doi-asserted-by":"publisher","award":["DP2-DK121328"],"award-info":[{"award-number":["DP2-DK121328"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"WiSE Major Support Award","award":["DP2-DK121328"],"award-info":[{"award-number":["DP2-DK121328"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The majority of clear cell renal cell carcinomas (ccRCCs) are characterized by mutations in the Von Hippel\u2013Lindau (VHL) tumor suppressor gene, which leads to the stabilization and accumulation of the HIF2\u03b1 transcription factor that upregulates key oncogenic pathways that promote glucose metabolism, cell cycle progression, angiogenesis, and cell migration. Although FDA-approved HIF2\u03b1 inhibitors for treating VHL disease-related ccRCC are available, these therapies are associated with significant toxicities such as anemia and hypoxia. To improve ccRCC-specific drug delivery, peptide amphiphile micelles (PAMs) were synthesized incorporating peptides targeted to the CD70 marker expressed by ccRCs and anti-HIF2\u03b1 siRNA, and the ability of HIF2\u03b1-CD27 PAMs to modulate HIF2\u03b1 and its downstream targets was evaluated in human ccRCC patient-derived cells. Cell cultures were derived from eight human ccRCC tumors and the baseline mRNA expression of HIF2A and CD70, as well as the HIF2\u03b1 target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 were first determined. As expected, each gene was overexpressed by at least 63% of all samples compared to normal kidney proximal tubule cells. Upon incubation with HIF2\u03b1-CD27 PAMs, a 50% increase in ccRCC-binding was observed upon incorporation of a CD70-targeting peptide into the PAMs, and gel shift assays demonstrated the rapid release of siRNA (&gt;80% in 1 h) under intracellular glutathione concentrations, which contributed to ~70% gene knockdown of HIF2\u03b1 and its downstream genes. Further studies demonstrated that knockdown of the HIF2\u03b1 target genes SLC2A1, CCND1, VEGFA, CXCR4, and CXCL12 led to inhibition of their oncogenic functions of glucose transport, cell proliferation, angiogenic factor release, and cell migration by 50\u201380%. Herein, the development of a nanotherapeutic strategy for ccRCC-specific siRNA delivery and its potential to interfere with key oncogenic pathways is presented.<\/jats:p>","DOI":"10.3390\/molecules27238457","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T06:29:09Z","timestamp":1670221749000},"page":"8457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["CD70-Targeted Micelles Enhance HIF2\u03b1 siRNA Delivery and Inhibit Oncogenic Functions in Patient-Derived Clear Cell Renal Carcinoma Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Noah","family":"Trac","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Seok","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila Izzy","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy","family":"Caliliw","sequence":"additional","affiliation":[{"name":"Institute of Urologic Oncology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Ohtake","sequence":"additional","affiliation":[{"name":"Institute of Urologic Oncology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Shuch","sequence":"additional","affiliation":[{"name":"Institute of Urologic Oncology, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7726-5555","authenticated-orcid":false,"given":"Eun Ji","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Department of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.14740\/wjon1279","article-title":"Epidemiology of Renal Cell Carcinoma","volume":"11","author":"Padala","year":"2020","journal-title":"World J. 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