Targeting and Energy‐Depleting Biomimetic Nanoparticles for Enhancing Combined Chemo‐Sonodynamic Therapy Against Esophageal Cancer

ABSTRACT Esophageal cancer is the seventh leading cause of cancer death, and the energy depletion in cancer cells can be achieved through synergistic therapy. The integration of sonodynamic therapy and chemotherapy offers a promising comprehensive treatment strategy for esophageal cancer. However, a significant challenge lies in the efficient delivery of sound sensitizers and therapeutic agents. Herein, we present an energy‐depleting biomimetic Zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticle with high encapsulation efficiencies for the sonosensitizer Indocyanine green (ICG) and the chemotherapeutic agent Doxorubicin (DOX). By coating the nanoplatform with esophageal cancer cell membranes, we achieve enhanced homologous targeting to esophageal cancer cells, termed ICG/DOX/ZIF‐8@M. In vitro and in vivo experiments demonstrated significant inhibition of tumor growth when treated with ICG/DOX/ZIF‐8@M and ultrasonic stimulation. Single‐cell RNA sequencing and mechanistic studies further elucidated the downregulation of energy metabolism‐related pathways, including glutamine metabolism and glycolysis, which contribute to the enhanced efficacy of the combined therapy. Targeting and energy‐depleting biomimetic ICG DOX/ZIF‐8@M nanoparticles represent a promising strategy for esophageal cancer therapy.