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Although gene therapy holds promise for overcoming such resistance, identifying effective radiosensitization targets and developing efficient gene delivery systems remain practically challenging. In this study, transcriptomic analysis of radiotherapy\u2010treated prostate cancer cells revealed a marked upregulation of DNA polymerase delta subunit 4 (POLD4), a target that has not been systematically studied. To evaluate the potential of POLD4 for overcoming radioresistance, CRISPR\u2010Cas9\u2010based plasmids along with ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) were encapsulated within cationic liposomes for achieving an MRI\u2010trackable gene delivery platform (plasmid and iron oxide co\u2010loaded liposomes, termed PIO@Lipo). Comprehensive in vitro and in vivo studies demonstrated that PIO@Lipo enabled efficient POLD4 knockdown. Furthermore, PIO@Lipo synergized with radiotherapy to induce extensive DNA damage, promote tumor cell apoptosis, and remodel the immunosuppressive microenvironment. Notably, PIO@Lipo displayed superior MRI contrast enhancement capability and passive tumor targeting ability. In conclusion, this study has identified POLD4 as a potent target for radiosensitization, capable of disrupting DNA damage\u2010repair homeostasis through MRI\u2010monitored gene editing, thereby offering a promising strategy to enhance the efficacy of radiotherapy in prostate cancer.<\/jats:p>","DOI":"10.1002\/advs.202519704","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T15:32:23Z","timestamp":1767799943000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CRISPR\u2010Cas9\u2010Loaded Theranostic Liposomes for Enhancing Radiosensitization of Prostate Cancer through POLD4 Gene Editing under Real\u2010Time MRI Monitoring"],"prefix":"10.1002","volume":"13","author":[{"given":"Xuhui","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Radiology Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai P. R. 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