Metabolic Trojan Horse: Multivalent Glucose Ligand Modified Near-Infrared-Absorbing Gold Nanorods for Targeted Photothermal Therapy

Nanoparticle-based photothermal therapy (PTT) provides localized tumor ablation but remains limited by off-target accumulation and the need for high systemic doses. To address these challenges, we developed gold nanorods (AuNRs) coated with a multivalent glucose ligand (mvGlu-AuNR) that engages glucose transporter type 1 (GLUT1) for selective tumor delivery. This design leverages the Warburg effect, using GLUT1 as a metabolic Trojan horse to enter glycolytic cancer cells. In 4T1 breast cancer models, mvGlu-AuNR showed an 8-fold increase in gold content and a 3-fold rise in photoacoustic signal compared to nontargeted controls. Notably, mvGlu-AuNRs converted light to heat more efficiently than mPEG-AuNRs under identical irradiation conditions. ICP-MS analysis confirmed tumor-to-liver ratios ranging from 1.56 to 4.88, which is consistent with strong tumor localization and minimal hepatic uptake. At a systemic dose of 1 mg/kg, mvGlu-AuNRs enabled efficient tumor heating and slowed tumor growth without signs of off-target toxicity. These findings establish metabolic targeting as an effective strategy to enhance PTT specificity, reduce off-target exposure, and enable markedly lower gold dosing.