NIR-Activated NO-Propelled Nanomotors for Deep Tumor Penetration and DNA-Repair Sensitized Photothermal Therapy of Prostate Cancer

NIR-Activated NO-Propelled Nanomotors for Deep Tumor Penetration and DNA-Repair Sensitized Photothermal Therapy of Prostate Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article NIR-Activated NO-Propelled Nanomotors for Deep Tumor Penetration and DNA-Repair Sensitized Photothermal Therapy of Prostate Cancer Jie He, Xiaoli Zhang, Qiqi Yang, Ji Sun, Yu An, Kehua Jiang, Fa Sun, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9091462/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 12 You are reading this latest preprint version Abstract Photothermal therapy (PTT) for solid prostate cancer (PCa) is often limited by poor intratumoral penetration and rapid DNA repair. Herein, we engineered a PSMA-targeted gas nanomotor that couple deep tumor penetration with DNA repair sensitization for enhanced photothermal/NO therapy. BLM helicase inhibitor ML216 and nitric oxide donor BNN6 were co-encapsulated with phase-change material and loaded into single-pore hollow polydopamine nanoparticles, followed by surface conjugation with anti-PSMA nanobodies (VHH) to yield M/B@PDA‑VHH NPs. VHH-mediated recognition confers active targeting toward PSMA-positive PCa cells. Under near-infrared irradiation, the nanoparticles show high photothermal conversion and trigger on-demand release of NO and ML216. NO generation propels nanomotor movement, markedly improving transport across endothelial barriers, penetration into 3D tumor spheroids, and distribution in PCa tissues in vivo. Photothermal/NO treatment induces DNA damage and promote apoptosis. Released ML216 inhibits BLM helicase, leading to replication fork stalling and accumulation of double-strand breaks, and concomitantly suppresses AKT/mTOR signaling via dephosphorylation of p‑AKT and p‑PRAS40. These effects disrupt DNA repair and amplify oxidative damage, restoring therapeutic sensitivity. In vitro and in vivo studies show strong tumor growth inhibition with minimal systemic toxicity. This gas-propelled platform offers a strategy to overcome stromal barriers and resistance in solid PCa. Controlled release Nitric oxide BLM helicase inhibition Deep penetration Prostate cancer Full Text Additional Declarations No competing interests reported. Supplementary Files SupportingInformation.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 12 Apr, 2026 Reviews received at journal 12 Apr, 2026 Reviews received at journal 10 Apr, 2026 Reviews received at journal 31 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviewers agreed at journal 15 Mar, 2026 Reviewers agreed at journal 15 Mar, 2026 Reviewers invited by journal 15 Mar, 2026 Editor assigned by journal 14 Mar, 2026 Submission checks completed at journal 14 Mar, 2026 First submitted to journal 11 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9091462","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":607033958,"identity":"ce23cbc8-1947-4e63-9a97-25415265a589","order_by":0,"name":"Jie He","email":"","orcid":"","institution":"Guizhou University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"He","suffix":""},{"id":607033959,"identity":"c5431713-17ac-4ac4-945a-905fef1f8ae6","order_by":1,"name":"Xiaoli Zhang","email":"","orcid":"","institution":"Guizhou University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoli","middleName":"","lastName":"Zhang","suffix":""},{"id":607033960,"identity":"8f56c82e-0e80-46ba-8fd5-9826af97b578","order_by":2,"name":"Qiqi Yang","email":"","orcid":"","institution":"Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiqi","middleName":"","lastName":"Yang","suffix":""},{"id":607033961,"identity":"36e1cd6a-565e-4763-89e0-c5451070971d","order_by":3,"name":"Ji Sun","email":"","orcid":"","institution":"Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ji","middleName":"","lastName":"Sun","suffix":""},{"id":607033962,"identity":"6e1dc2a1-d819-4bd9-8425-0f36154c57a0","order_by":4,"name":"Yu An","email":"","orcid":"","institution":"Guizhou Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"An","suffix":""},{"id":607033963,"identity":"216e6208-75ef-49a3-9b27-3f441d40ee66","order_by":5,"name":"Kehua Jiang","email":"","orcid":"","institution":"Guizhou Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kehua","middleName":"","lastName":"Jiang","suffix":""},{"id":607033964,"identity":"352c76f7-5da4-4715-b807-e15d08a99bad","order_by":6,"name":"Fa Sun","email":"","orcid":"","institution":"Guizhou University","correspondingAuthor":false,"prefix":"","firstName":"Fa","middleName":"","lastName":"Sun","suffix":""},{"id":607033965,"identity":"a6746834-387b-4ca6-863c-ff378ca9629b","order_by":7,"name":"Janguo Zhu","email":"","orcid":"","institution":"Guizhou University","correspondingAuthor":false,"prefix":"","firstName":"Janguo","middleName":"","lastName":"Zhu","suffix":""},{"id":607033966,"identity":"6e38eec2-f675-4936-9722-83d66decdb9e","order_by":8,"name":"Kun Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBACxobDBwwkKv7J8ROthbnxWEKBxZkDxpINxGphbz5j8KGy7UCiwQFitfC2HUvccLPtToLx8eQNDD8qthHWItlz+LDhjHPP8szOPCtg7Dlzm7AWwxnH0owlypiLzW7kGDAzthGhxf7+G/Pff9iYEzfPIFYLY8MZAwOJtsOJGySI13IswUDiDNBxQL8cJMov0Ki0keNvT9744EcFEVqQQALxUYPQQqqOUTAKRsEoGCEAAHCdR7DPMEaIAAAAAElFTkSuQmCC","orcid":"","institution":"Guizhou Provincial People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kun","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2026-03-11 07:41:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9091462/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9091462/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105562498,"identity":"75ce6753-8ec0-4cce-9875-c50b5bf7fccd","added_by":"auto","created_at":"2026-03-27 12:41:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2485267,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscripts.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9091462/v1_covered_962ff675-c292-478a-a44c-16c731e78786.pdf"},{"id":104840411,"identity":"7085dbee-99d8-43c9-bbbd-ca81fdf80977","added_by":"auto","created_at":"2026-03-17 19:17:01","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":3851876,"visible":true,"origin":"","legend":"","description":"","filename":"SupportingInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-9091462/v1/0866e99bfb8f7b21da93bc93.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"NIR-Activated NO-Propelled Nanomotors for Deep Tumor Penetration and DNA-Repair Sensitized Photothermal Therapy of Prostate Cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-nanobiotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jnan","sideBox":"Learn more about [Journal of Nanobiotechnology](http://jnanobiotechnology.biomedcentral.com)","snPcode":"12951","submissionUrl":"https://submission.nature.com/new-submission/12951/3","title":"Journal of Nanobiotechnology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Controlled release, Nitric oxide, BLM helicase inhibition, Deep penetration, Prostate cancer","lastPublishedDoi":"10.21203/rs.3.rs-9091462/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9091462/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePhotothermal therapy (PTT) for solid prostate cancer (PCa) is often limited by poor intratumoral penetration and rapid DNA repair. Herein, we engineered a PSMA-targeted gas nanomotor that couple deep tumor penetration with DNA repair sensitization for enhanced photothermal/NO therapy. BLM helicase inhibitor ML216 and nitric oxide donor BNN6 were co-encapsulated with phase-change material and loaded into single-pore hollow polydopamine nanoparticles, followed by surface conjugation with anti-PSMA nanobodies (VHH) to yield M/B@PDA‑VHH NPs. VHH-mediated recognition confers active targeting toward PSMA-positive PCa cells. Under near-infrared irradiation, the nanoparticles show high photothermal conversion and trigger on-demand release of NO and ML216. NO generation propels nanomotor movement, markedly improving transport across endothelial barriers, penetration into 3D tumor spheroids, and distribution in PCa tissues in vivo. Photothermal/NO treatment induces DNA damage and promote apoptosis. Released ML216 inhibits BLM helicase, leading to replication fork stalling and accumulation of double-strand breaks, and concomitantly suppresses AKT/mTOR signaling via dephosphorylation of p‑AKT and p‑PRAS40. These effects disrupt DNA repair and amplify oxidative damage, restoring therapeutic sensitivity. In vitro and in vivo studies show strong tumor growth inhibition with minimal systemic toxicity. This gas-propelled platform offers a strategy to overcome stromal barriers and resistance in solid PCa.\u003c/p\u003e","manuscriptTitle":"NIR-Activated NO-Propelled Nanomotors for Deep Tumor Penetration and DNA-Repair Sensitized Photothermal Therapy of Prostate Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-17 19:16:56","doi":"10.21203/rs.3.rs-9091462/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-13T02:31:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-13T02:28:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-10T04:33:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-31T04:30:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"81728353000941666335683196316866384860","date":"2026-03-16T15:16:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219362362874845976017046033685868148088","date":"2026-03-16T04:40:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86864548735316148021396956386451106799","date":"2026-03-16T02:04:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139859392683445138943507761338566313051","date":"2026-03-16T02:04:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-15T21:13:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-14T05:30:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-14T05:29:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Nanobiotechnology","date":"2026-03-11T07:28:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-nanobiotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jnan","sideBox":"Learn more about [Journal of Nanobiotechnology](http://jnanobiotechnology.biomedcentral.com)","snPcode":"12951","submissionUrl":"https://submission.nature.com/new-submission/12951/3","title":"Journal of Nanobiotechnology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68742b19-ea0e-4d1e-b456-6dfb3b2ef632","owner":[],"postedDate":"March 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T02:38:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-17 19:16:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9091462","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9091462","identity":"rs-9091462","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}