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A hierarchically targeted, reactive oxygen species (ROS)-responsive micelle system was engineered to synergistically co-deliver the hydrophobic drugs sorafenib and dehydrodiisoeugenol using a ROS-sensitive thioacetal ketone bond and glycyrrhetinic acid targeting. TK-GA-Sof/Deh-Ms showed high encapsulation and stability, with 48 h release of Sof and Deh at 49.67% and 43.90%. SynergyFinder2.0 yielded a ZIP score of 6.339, and TK-GA-Sof/Deh-Ms reduced IC50 to 13.21 μM while promoting M1 polarization and suppressing M2 activation.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/dual-functional-micelles-for-codelivery-of-sorafenib-and-dehydrodiisoeugenol-in-treatment-of-hepatocellular-carcinoma/648390/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/dual-functional-micelles-for-codelivery-of-sorafenib-and-dehydrodiisoeugenol-in-treatment-of-hepatocellular-carcinoma/648390.png","ImageObject",300,407,{"name":42,"@type":43},"\tCallum ","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-24","2026-10-23",true,{"@type":52,"interactionType":53,"userInteractionCount":22},"InteractionCounter",{"@type":54},"ViewAction",{"@type":56,"mainEntity":57},"FAQPage",[58,64,68],{"name":59,"@type":60,"acceptedAnswer":61},"Why is chemotherapy less effective for hepatocellular carcinoma?","Question",{"text":62,"@type":63},"Chemotherapeutic effectiveness is limited by the tumor microenvironment, which contains extensive infiltration by immune cells that reduce the therapeutic impact of drug agents.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"What design features enable the dual-functional micelle system?",{"text":67,"@type":63},"The system integrates a ROS-sensitive bond (thioacetal ketones) and glycyrrhetinic acid targeting to support hierarchically targeted, ROS-responsive co-delivery of sorafenib and dehydrodiisoeugenol.",{"name":69,"@type":60,"acceptedAnswer":70},"How do the micelles affect macrophage polarization and antitumor activity?",{"text":71,"@type":63},"Dehydrodiisoeugenol promotes M1 macrophage polarization while inhibiting M2 macrophage activation. 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Nano Mater. 2025, 8, 5355−5372  \nRead Online  \n\n|  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- |\n| ACCESS   | Metrics & More |  |  Article Recommendations |  | *sı Supporting Information |\n\nABSTRACT: Hepatocellular carcinoma (HCC) represents a significant health challenge that requires urgent attention, primarily due to the limited application of chemotherapeutic drugs. This limitation arises from the high infiltration of immune cells within the tumor microenvironment, which diminishes the effectiveness of the therapeutic agents. Consequently, exploring the combination of drug therapy with the M1 polarization mechanism is considered a promising strategy to address this issue. In this study, we designed a hierarchically targeted micelle system responsive to reactive oxygen species (ROS), enabling the synergistic delivery of the hydrophobic drugs sorafenib (Sof) and dehydrodii  \nsoeugenol (Deh) through the integration of a ROS-sensitive bond (thioacetal ketones, TK) and a specific targeting group (glycyrrhetinic acid, GA). The results demonstrated that TK-GA-Sof/Deh-Ms exhibited excellent encapsulation efficiency and stability. The cumulative release rates of Sof and Deh from TK-GA-Sof/Deh-Ms at 48 h were recorded as 49.67 ± 0.02% and 43.90 ± 0.01%, respectively. The online SynergyFinder2.0 software was used to calculate a ZIP synergy score of 6.339 for Sof and Deh, indicating synergy. The combination showed a more significant antitumor effect. The IC50 value of TK-GA-Sof/Deh-Ms was 13.21 ± 1.36 μM. Notably, Deh not only promotes the polarization of M1 macrophages but also effectively inhibits the activation of M2 macrophages. In summary, this study introduces a stepwise-targeting micelle system for liver cancer that possesses dual functions 􀀁 tumor inhibition and macrophage regulation, thereby paving the way for innovative treatment strategies for hepatocellular carcinoma.  \nKEYWORDS: hepatocellular carcinoma, sorafenib, dehydrodiisoeugenol, tumor microenvironment-targeted micelles, macrophage polarization  \n1. INTRODUCTION  \nHepatocellular carcinoma (HCC) is the most common type of liver cancer, presenting a significant challenge to public health.1 The global incidence and mortality rates of HCC exhibit an uneven trend, primarily influenced by environmental factors, exposure to infection risks, availability of medical resources, and the effectiveness of early diagnosis and treatment. As the population ages and grows, the number of HCC cases continues to rise.2,3 HCC can be induced by factors such as viral hepatitis, excessive alcohol consumption, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).4,5 For early-stage hepatocellular carcinoma, local ablation, surgical resection, and liver transplantation are regarded as radical treatment options. Unfortunately, approximately 70% of patients experience HCC recurrence following surgery. Patients with advanced disease may benefit from new systemic therapies that demonstrate significant positive effects.6 It is estimated that around 50−60% of HCC patients will receive systemic therapy during the course of their illness, and the widespread availability of such treatments offers greater opportunities to enhance overall patient survival.7−9  \n© 2025 American Chemical Society  \nHCC can be categorized into inflammatory and noninflammatory types, with the inflammatory type comprising approximately 30% of HCC cases and characterized by extensive immune cell infiltration.10, 11 Tumor-associated macrophages (TAMs), which are the predominant tumor-infiltrating immune cells, can differentiate into M1-type antitumor phenotypes and M2-type ","cbCaitcPkDCvGptf","https://ap.wps.com/l/cbCaitcPkDCvGptf","pdf",5874734,24,"English","# ABSTRACT\n# 1. INTRODUCTION","[{\"question\":\"Why is chemotherapy less effective for hepatocellular carcinoma?\",\"answer\":\"Chemotherapeutic effectiveness is limited by the tumor microenvironment, which contains extensive infiltration by immune cells that reduce the therapeutic impact of drug agents.\"},{\"question\":\"What design features enable the dual-functional micelle system?\",\"answer\":\"The system integrates a ROS-sensitive bond (thioacetal ketones) and glycyrrhetinic acid targeting to support hierarchically targeted, ROS-responsive co-delivery of sorafenib and dehydrodiisoeugenol.\"},{\"question\":\"How do the micelles affect macrophage polarization and antitumor activity?\",\"answer\":\"Dehydrodiisoeugenol promotes M1 macrophage polarization while inhibiting M2 macrophage activation. Combined with sorafenib, the formulation shows a stronger antitumor effect and measurable synergy.\"}]","Dual-Functional Micelles for Codelivery of Sorafenib and Dehydrodiisoeugenol in Treatment of Hepatocellular Carcinoma | PDF",1792793318]