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In 10\u201320% of the cases, PCa progresses to an incurable, castration\u2010resistant stage. Castration\u2010resistant PCa cells often overexpress prostate\u2010specific membrane antigen (PSMA), a membrane protein that may serve as their Achilles' heel. Over the past decades, RNA\u2010based therapeutics have emerged as promising treatments for a vast array of diseases, including cancer. In this study, with the ultimate goal of developing a targeted therapy for PCa, lipid nanoparticles (LNPs) are decorated with an anti\u2010PSMA nanobody using click chemistry with a PEG\u2010lipid. Direct stochastic optical reconstruction microscopy (dSTORM) and cluster analysis confirm the presence of at least one nanobody on the surface of 80% of LNPs. These anti\u2010PSMA LNPs exhibit enhanced and specific uptake, and mRNA transfection in PSMA+ cancer cells both in vitro and in a Zebrafish (ZF) metastatic PCa xenograft model. Additionally, in a mouse PSMA\u2010positive xenograft model, systemic administration results in increased LNP accumulation, but not functional mRNA delivery. These findings underscore both the potential and the challenges of using a PSMA\u2010targeted lipid nanoparticle system for mRNA delivery into advanced prostate cancer tumors.<\/jats:p>","DOI":"10.1002\/adhm.202500605","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T06:20:04Z","timestamp":1751610004000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Nanobody\u2010Decorated Lipid Nanoparticles for Enhanced mRNA Delivery to Tumors In Vivo"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0366-9124","authenticated-orcid":false,"given":"Pol","family":"Escud\u00e9 Martinez de Castilla","sequence":"first","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7963-5732","authenticated-orcid":false,"given":"Vincenzo","family":"Verdi","sequence":"additional","affiliation":[{"name":"Institut de Psychiatrie et Neurosciences de Paris Universit\u00e9 Paris Cit\u00e9  INSERM 1266 Paris 75014 France"},{"name":"Laboratory of Cancer Biology and Genetics National Cancer Institute National Institutes of Health (NIH)  Bethesda MD 20892 United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7876-5018","authenticated-orcid":false,"given":"Willemijn","family":"de Voogt","sequence":"additional","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariona","family":"Estap\u00e9 Sent\u00ed","sequence":"additional","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold C.","family":"Koekman","sequence":"additional","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Rietveld","sequence":"additional","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"van Kempen","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangbing","family":"Yang","sequence":"additional","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"van Merris","sequence":"additional","affiliation":[{"name":"CDL Research University Medical Center Utrecht  Utrecht 3584CX The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Jenster","sequence":"additional","affiliation":[{"name":"Department of Urology Erasmus MC  Rotterdam 3015GD The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E.","family":"van Royen","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus MC University Medical Center Rotterdam  Rotterdam 3015GD The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel H.","family":"Fens","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS) Utrecht University  Utrecht 3584CG The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander A. 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