Myeloperoxidase/ASGPR Dual‐Targeting Self‐Amplifying Nanoplatform for Synergistic Anti‐Metastatic Therapy of Hepatocellular Carcinoma

ABSTRACT

Hepatocellular carcinoma (HCC) remains highly lethal due to a complex tumor microenvironment (TME) that limits therapeutic efficacy. Herein, a dual‐targeted nanotherapeutic platform (SC@GRT‐COF‐366) based on a covalent organic framework (COF‐366) is reported for synergistic HCC treatment. This multifunctional system integrates chemotherapy, photodynamic therapy, autophagy regulation, and TME remodeling to synergistically inhibit tumor metastasis. Gal‐D5HT‐modified nanoparticles achieve enhanced HCC targeting via myeloperoxidase (MPO)‐responsive aggregation in the inflammatory microenvironment and ASGPR‐mediated uptake. Upon light irradiation, COF‐366 generates singlet oxygen to induce tumor cell apoptosis and simultaneously enhances MPO expression and neutrophil infiltration, further amplifying MPO‐triggered nanoparticle aggregation and establishing a self‐amplifying retention‐therapy cascade. Meanwhile, co‐loaded 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‐targeted systems, resulting in a tumor growth inhibition rate of 93.5 ± 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‐based nanoplatform integrates dual‐targeted delivery, amplified tumor retention, and synergistic multimodal therapy, offering a promising strategy for advanced HCC treatment.