{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:08:01Z","timestamp":1789754881588,"version":"4.0.1"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nanchong City School Science and Technology Strategic Cooperation Project","award":["22SXQT 0294"],"award-info":[{"award-number":["22SXQT 0294"]}]},{"name":"Research and Development Program of North Sichuan Medical College","award":["CBY23-QNA51"],"award-info":[{"award-number":["CBY23-QNA51"]}],"id":[{"id":"https:\/\/ror.org\/05k3sdc46","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Guang\u2019an Science and Technology Bureau","award":["2022zdxjh18"],"award-info":[{"award-number":["2022zdxjh18"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    As a prevalent malignancy, liver cancer ranks as the third most common cause of cancer mortality globally. Within the tumor microenvironment, tumor-associated macrophages (TAMs) exhibit contrasting functional phenotypes: the anti-tumor M1 type and the pro-tumor M2 type. Reprogramming TAMs from the M2 to the M1 phenotype has emerged as a promising immunotherapeutic strategy. Here, we engineered a multi-nano therapeutic system, PAH@HMMDN@R848, by loading a TLR7\/8 agonist (R848) onto hollow MnO\n                    <jats:sub>2<\/jats:sub>\n                    nanoparticles (HMMDN) and coating with polyallylamine hydrochloride (PAH). In vitro, this system efficiently repolarized M2 macrophages to the M1 phenotype, evidenced by decreased CD206, Arg-1, IL-10 and increased CD80, iNOS, TNF-\u03b1 (P\u2009&lt;\u20090.05). Under acidic\/glutathione-rich conditions, HMMDN degraded to release Mn\n                    <jats:sup>2+<\/jats:sup>\n                    , which served as a T\n                    <jats:sub>1<\/jats:sub>\n                    -weighted MRI contrast agent with a high relaxivity (r\n                    <jats:sub>1<\/jats:sub>\n                    \u2009=\u20095.255 mM\n                    <jats:sup>-<\/jats:sup>\n                    <jats:sup>1<\/jats:sup>\n                    \u2009s\u2009\n                    <jats:sup>-<\/jats:sup>\n                    <jats:sup>1<\/jats:sup>\n                    ). Mechanistically, PAH@HMMDN@R848 activated both NF-\u03baB (via R848) and STING (via Mn\n                    <jats:sup>2+<\/jats:sup>\n                    ) pathways, leading to synergistic M1 polarization. In a subcutaneous H22 liver cancer mouse model, intratumoral injection of PAH@HMMDN@R848 significantly suppressed tumor growth (tumor inhibition rate 80.6%) without obvious systemic toxicity. Immunohistochemistry and cytokine analysis revealed that the treatment increased M1 macrophage infiltration (CD80\n                    <jats:sup>+<\/jats:sup>\n                    ) and reduced M2 macrophages (CD206\n                    <jats:sup>+<\/jats:sup>\n                    ) within tumors, along with elevated TNF-\u03b1\/iNOS and decreased IL-10\/Arg-1. This study presents a multifunctional nanoplatform capable of TAMs reprogramming and MRI diagnosis, offering a promising approach for liver cancer theranostics.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0358567","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:25:58Z","timestamp":1789752358000},"page":"e0358567","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming M2 macrophages via TLR7\/8 agonist-loaded hollow MnO2 nanovehicles to suppress the progression of liver cancer"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8899-2722","authenticated-orcid":true,"given":"Pei-pei","family":"He","sequence":"first","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]},{"name":"Innovation Centre for Science and Technology of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]},{"name":"Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, North Sichuan Medical College","place":["Nanchong, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-ju","family":"Hou","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]},{"name":"Innovation Centre for Science and Technology of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]},{"name":"Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, North Sichuan Medical College","place":["Nanchong, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-mei","family":"Li","sequence":"additional","affiliation":[{"name":"Innovation Centre for Science and Technology of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]},{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Ultrasound"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]},{"name":"Innovation Centre for Science and Technology of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An-Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]},{"name":"Innovation Centre for Science and Technology of North Sichuan Medical College","place":["Nanchong, Sichuan, China"]},{"name":"Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, North Sichuan Medical College","place":["Nanchong, Sichuan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan-you","family":"Miao","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Feng","family":"Yang","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-hong","family":"Yu","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Ultrasound"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Af\ufb01liated Hospital of North Sichuan Medical College","place":["Nanchong, Sichuan, China"],"department":["Department of Radiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"pone.0358567.ref001","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"F Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"issue":"6","key":"pone.0358567.ref002","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"H Rumgay","year":"2022","journal-title":"J Hepatol"},{"issue":"1","key":"pone.0358567.ref003","doi-asserted-by":"crossref","first-page":"102406","DOI":"10.1016\/j.jceh.2024.102406","article-title":"Evolving global etiology of hepatocellular carcinoma (HCC): insights and trends for 2024","volume":"15","author":"A Koshy","year":"2025","journal-title":"J Clin Exp Hepatol"},{"issue":"6","key":"pone.0358567.ref004","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1159\/000509424","article-title":"Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition)","volume":"9","author":"J Zhou","year":"2020","journal-title":"Liver 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He","year":"2020","journal-title":"Biomed Res Int"},{"issue":"4","key":"pone.0358567.ref011","doi-asserted-by":"crossref","first-page":"596","DOI":"10.4251\/wjgo.v15.i4.596","article-title":"Role of tumor-associated macrophages in common digestive system malignant tumors","volume":"15","author":"Y Shen","year":"2023","journal-title":"World J Gastrointest Oncol"},{"issue":"1","key":"pone.0358567.ref012","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41392-025-02325-5","article-title":"Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments","volume":"10","author":"J Xu","year":"2025","journal-title":"Signal Transduct Target Ther"},{"issue":"10","key":"pone.0358567.ref013","doi-asserted-by":"crossref","first-page":"11049","DOI":"10.1002\/cam4.5489","article-title":"Antitumor therapy for breast cancer: Focus on tumor-associated macrophages and nanosized drug delivery systems","volume":"12","author":"C 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Bioelectron"},{"issue":"17","key":"pone.0358567.ref023","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1039\/D3TB02844E","article-title":"Manganese-based nanomaterials promote synergistic photo-immunotherapy: green synthesis, underlying mechanisms, and multiple applications","volume":"12","author":"Y Cao","year":"2024","journal-title":"J Mater Chem B"},{"key":"pone.0358567.ref024","doi-asserted-by":"crossref","first-page":"0158","DOI":"10.34133\/bmr.0158","article-title":"Mechanisms and Applications of Manganese-Based Nanomaterials in Tumor Diagnosis and Therapy","volume":"29","author":"X Ma","year":"2025","journal-title":"Biomater Res"},{"issue":"11","key":"pone.0358567.ref025","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s41422-020-00395-4","article-title":"Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy","volume":"30","author":"M Lv","year":"2020","journal-title":"Cell Res"},{"issue":"11","key":"pone.0358567.ref026","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/s41565-021-00962-9","article-title":"Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy","volume":"16","author":"X Sun","year":"2021","journal-title":"Nat Nanotechnol"},{"key":"pone.0358567.ref027","doi-asserted-by":"crossref","DOI":"10.1002\/wnan.1720","article-title":"Multifunctional MnO2 nanoparticles for tumor microenvironment modulation and cancer therapy","volume":"13","author":"G Yang","year":"2021","journal-title":"Wiley Interdiscip Rev Nanomed Nanobiotechnol"},{"issue":"40","key":"pone.0358567.ref028","doi-asserted-by":"crossref","first-page":"44407","DOI":"10.1021\/acsami.0c08473","article-title":"Nanoparticle Delivery of MnO2 and Antiangiogenic Therapy to Overcome Hypoxia-Driven Tumor Escape and Suppress Hepatocellular Carcinoma","volume":"12","author":"C-C Chang","year":"2020","journal-title":"ACS Appl Mater Interfaces"},{"issue":"1","key":"pone.0358567.ref029","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3390\/ani4010035","article-title":"Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research","volume":"4","author":"C Kilkenny","year":"2014","journal-title":"Animals"},{"key":"pone.0358567.ref030","unstructured":"National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington (DC): National Academies Press (US). 2011."},{"key":"pone.0358567.ref031","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.actbio.2022.01.019","article-title":"Manganese-based multifunctional nanoplatform for dual-modal imaging and synergistic therapy of breast cancer","volume":"141","author":"C Zhu","year":"2022","journal-title":"Acta Biomater"},{"issue":"3","key":"pone.0358567.ref032","doi-asserted-by":"crossref","first-page":"112185","DOI":"10.1016\/j.celrep.2023.112185","article-title":"NF-\u03baB activation enhances STING signaling by altering microtubule-mediated STING trafficking","volume":"42","author":"L Zhang","year":"2023","journal-title":"Cell Rep"},{"issue":"1","key":"pone.0358567.ref033","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12943-020-01247-w","article-title":"cGAS-STING pathway in cancer biotherapy","volume":"19","author":"Y Wang","year":"2020","journal-title":"Mol Cancer"},{"issue":"38","key":"pone.0358567.ref034","article-title":"A Biomimetic Polymer Magnetic Nanocarrier Polarizing Tumor-Associated Macrophages for Potentiating Immunotherapy","volume":"16","author":"L Liu","year":"2020","journal-title":"Small"},{"key":"pone.0358567.ref035","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.ebiom.2018.02.009","article-title":"Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity","volume":"30","author":"F Wang","year":"2018","journal-title":"EBioMedicine"},{"issue":"31","key":"pone.0358567.ref036","doi-asserted-by":"crossref","first-page":"9881","DOI":"10.1021\/jacs.6b04299","article-title":"\u201cManganese Extraction\u201d Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles","volume":"138","author":"L Yu","year":"2016","journal-title":"J Am Chem Soc"},{"key":"pone.0358567.ref037","doi-asserted-by":"crossref","first-page":"112322","DOI":"10.1016\/j.ejrad.2025.112322","article-title":"Gadolinium concentration dependent signal enhancement profiles using routine clinical sequences with gadopiclenol, gadoterate, gadobutrol, and gadoxetate at 1.5, 3 and 7 Tesla","volume":"191","author":"T Marth","year":"2025","journal-title":"Eur J Radiol"},{"issue":"12","key":"pone.0358567.ref038","doi-asserted-by":"crossref","DOI":"10.1002\/mabi.202500388","article-title":"High-Integrity Nanoformulation of Resiquimod (R848) for Dual Autophagy Activation and PD-L1 Modulation in Triple-Negative Breast Cancer","volume":"25","author":"A Salem","year":"2025","journal-title":"Macromol Biosci"},{"key":"pone.0358567.ref039","doi-asserted-by":"crossref","first-page":"902820","DOI":"10.3389\/fonc.2022.902820","article-title":"Mouse Models of Hepatocellular Carcinoma: Classification, Advancement, and Application","volume":"12","author":"S Liu","year":"2022","journal-title":"Front Oncol"},{"issue":"1","key":"pone.0358567.ref040","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1038\/s41467-022-30543-w","article-title":"Nanoparticle-enhanced radiotherapy synergizes with PD-L1 blockade to limit post-surgical cancer recurrence and metastasis","volume":"13","author":"X Guan","year":"2022","journal-title":"Nat Commun"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0358567","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:26:05Z","timestamp":1789752365000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0358567"}},"subtitle":[],"editor":[{"given":"Bruno Lourenco","family":"Diaz","sequence":"first","affiliation":[{"name":"Universidade Federal do Rio de Janeiro","place":["BRAZIL"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0358567","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]}}}