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

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.