Resveratrol-Loaded Responsive Core–Shell Tecto Dendrimers Potentiate Hepatocellular Carcinoma Therapy

Biomaterials Research, vol. 30, pp. 0428

Abstract

Hepatocellular carcinoma (HCC) exhibits profound metabolic reprogramming, particularly enhanced glycolytic activity, which represents a therapeutic vulnerability. However, the remarkable adaptability of HCC metabolism allows tumor cells to compensate for metabolic disturbances and preserve cellular homeostasis, reducing the effectiveness of metabolism-targeted strategies. Therefore, strategies sustaining metabolic perturbation beyond tumor adaptive capacity are needed. Herein, we developed a pH-responsive zwitterion-modified core-shell tecto dendrimer nanocarrier (CSTD-PS) for resveratrol (Res) delivery to overcome these limitations and potentiate HCC therapy. CSTD-PS was constructed through dynamic boronate ester-mediated assembly and zwitterionic surface modification, enabling Res encapsulation and pH-responsive release. After Res encapsulation, Res@CSTD-PS exhibited enhanced cellular uptake and nanocarrier-associated tumor localization, resulting in superior antitumor efficacy in HCC models compared with free Res. Mechanistically, Res@CSTD-PS suppressed glycolytic regulators, including hexokinase 2, glucose transporter 1, and pyruvate kinase M2, accompanied by enhanced stress responses (glucose-regulated protein 78 and nuclear factor erythroid 2-related factor 2) and p53/caspase-3-associated apoptotic signaling. Res@CSTD-PS also reduced programmed death-ligand 1 expression, suggesting potential attenuation of immune-evasive characteristics. Collectively, this study introduces a strategy enabled by intelligent dendrimer-based nanomedicine, providing a promising approach for enhancing natural compound-based therapy against HCC.

Authors 10

1. Wenchao Liu

   Shandong First Medical University

   Affiliation as printed

   Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

2. Junjie Liu Aachen DWI - Leibniz Institute for Interactive Materials Institute for Technical and Macromolecular Chemistry

   DWI – Leibniz Institute for Interactive Materials

   Affiliation as printed

   DWI-Leibniz-Institute for Interactive Materials, Institute for Technical and Macromolecular Chemistry, RWTH Aachen University, Aachen 52074, Germany

3. 鄭鎭澤

   Shandong First Medical University

   Affiliation as printed

   Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

4. Wenqing Man

   Shandong First Medical University

   Affiliation as printed

   Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

5. Xiaoyang Zhang

   Shandong First Medical University

   Affiliation as printed

   Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

6. Xiaoyi Zheng

   Shandong First Medical University

   Affiliation as printed

   Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

7. Yupeng Wang

   Shandong First Medical University

   Affiliation as printed

   Biomedical Sciences College & Shandong Medical Biotechnology Research Center, National Health Commission Key Laboratory of Biotechnology Drugs, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

8. Yao Shi

   Shandong First Medical University

   Affiliation as printed

   Biomedical Sciences College & Shandong Medical Biotechnology Research Center, National Health Commission Key Laboratory of Biotechnology Drugs, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

9. Qinghai Lin

   Shandong First Medical University

   Affiliation as printed

   Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

10. Cong Song

    Shandong First Medical University

    Affiliation as printed

    Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China

    Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China