Glucose-responsive enzymatic biomimetic nanodots for H₂O₂ self-supplied catalytic photothermal/chemodynamic...

Photothermal therapy (PTT) combined with chemodynamic therapy (CDT) presents an appealing complementary anti-tumor strategy, wherein PTT accelerates the production of reactive oxygen species (ROS) in CDT and CDT eliminates residual tumor tissues that survive from PTT treatment. However, nanomaterials utilized in PTT/CDT are limited by non-specific damage to the entire organism. Herein, a glucose-responsive enzymatic Fe@HRP-ABTS/GOx nanodot is judiciously designed for tumor-specific PTT/CDT via a simple and clean protein-templated biomimetic mineralization synthesis. By oxidizing glucose in tumor cells, glucose oxidase (GOx) activates glucose-responsive tumor therapy and increases the concentration of H₂O₂ at the tumor site. More importantly, the self-supplied peroxide hydrogen (H₂O₂) can convert ABTS (2,2'-Hydrazine-bis(3-ethylbenzothiazoline-6-sulfonic acid) diamine salt) into oxidized ABTS (oxABTS) through horseradish peroxidase (HRP) catalysis for PTT and photoacoustic (PA) imaging. Furthermore, the Fe²⁺ arising from the reduction of Fe³⁺ by overexpressed GSH reacts with H₂O₂ to generate intensely reactive •OH through the Fenton reaction, concurrently depleting GSH and inducing efficient tumor CDT. The in vitro and in vivo experiments demonstrate superior cancer cell killing and tumor eradication effect of Fe@HRP-ABTS/GOx nanodot under near-infrared (NIR) laser irradiation. Collectively, the nanodots provide mutually reinforcing catalytic PTT/CDT anti-tumor strategies for treating liver cancer and potentially other malignancies. STATEMENT OF SIGNIFICANCE: Combinatorial antitumor therapy with nanomedicines presents great prospects for development. However, the limitation of non-specific damage to normal tissues hinders its further clinical application. In this work, we fabricated tumor-selective biomimetic Fe@HRP-ABTS/GOx nanodots for H₂O₂ self-supplied catalytic photothermal/chemodynamic therapy of tumors. The biomimetic synthesis strategy provides the nanodots with enzymatic activity in response to glucose to produce H₂O₂. The self-supplied H₂O₂ initiates photothermal therapy with oxidized ABTS and enhances chemodynamic therapy through simultaneous •OH generation and GSH depletion. Our work provides a new paradigm for developing tumor-selective catalytic nanomedicines and will guide further clinical translation of the enzymatic biomimetic synthesis strategy.