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Herein, a dual\u2010targeted nanotherapeutic platform (SC@GRT\u2010COF\u2010366) based on a covalent organic framework (COF\u2010366) is reported for synergistic HCC treatment. This multifunctional system integrates chemotherapy, photodynamic therapy, autophagy regulation, and TME remodeling to synergistically inhibit tumor metastasis. Gal\u2010D5HT\u2010modified nanoparticles achieve enhanced HCC targeting via myeloperoxidase (MPO)\u2010responsive aggregation in the inflammatory microenvironment and ASGPR\u2010mediated uptake. Upon light irradiation, COF\u2010366 generates singlet oxygen to induce tumor cell apoptosis and simultaneously enhances MPO expression and neutrophil infiltration, further amplifying MPO\u2010triggered nanoparticle aggregation and establishing a self\u2010amplifying retention\u2010therapy cascade. Meanwhile, co\u2010loaded sorafenib and chloroquine enable combined chemotherapy and autophagy inhibition, effectively overcoming drug resistance. In vivo results demonstrate significantly enhanced and prolonged tumor accumulation compared with single\u2010targeted systems, resulting in a tumor growth inhibition rate of 93.5 \u00b1 1.02% in subcutaneous models and effective suppression of lung metastasis in orthotopic HCC models. Notably, treatment markedly reduces neutrophil extracellular traps (NETs) formation, indicating favorable remodeling of the tumor immune microenvironment. Collectively, this multifunctional COF\u2010based nanoplatform integrates dual\u2010targeted delivery, amplified tumor retention, and synergistic multimodal therapy, offering a promising strategy for advanced HCC treatment.<\/jats:p>","DOI":"10.1002\/smll.74938","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T07:50:28Z","timestamp":1786175428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myeloperoxidase\/ASGPR Dual\u2010Targeting Self\u2010Amplifying Nanoplatform for Synergistic Anti\u2010Metastatic Therapy of Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"22","author":[{"given":"Le","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology Jiangnan University  Wuxi People's Republic of China"},{"name":"Department of Biomolecular Systems Max Planck 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