GE11‐Modified Red Blood Cell Membrane Nanoprodrug for ROS‐Responsive Synergistic Photothermal–Chemotherapy of Esophageal Cancer

Esophageal cancer (EC) remains a highly aggressive malignancy with limited therapeutic options and poor prognosis. To address the shortcomings of conventional therapies, we developed a biomimetic, reactive oxygen species (ROS)-responsive nanoprodrug for synergistic photothermal-chemotherapy of EC. Tannic acid and ellagic acid were chemically linked via boronate ester bonds to form a polyphenol-based nanoparticle (TPE). The epidermal growth factor receptor (EGFR)-targeting peptide GE11 was subsequently introduced onto red blood cell membranes (RBCM) to obtain GE11-RBCM, which was then used to cloak the TPE nanoparticles, yielding GE11-RBCM@TPE. The resulting nanoplatform exhibited excellent photothermal conversion capability under near-infrared irradiation and selectively released the therapeutic payload in response to elevated ROS levels within the tumor microenvironment. In vitro studies showed enhanced cellular uptake in EGFR-overexpressing EC cells and markedly increased cell death following combined photothermal and chemotherapeutic treatment. In vivo, GE11-RBCM@TPE significantly inhibited tumor growth with negligible systemic toxicity and prolonged blood circulation. Transcriptomic analysis further revealed up-regulation of pro-apoptotic (PER1, HK2, BMF, DAPK2) and autophagy-related genes (ATP6V0D2, HDAC10, BNIP3, DEPP1, ATG9B, NAT16), while SQSTM1 and IL6 were down-regulated, indicating simultaneous activation of apoptosis and autophagy. These findings suggest that GE11-RBCM@TPE represents a promising strategy for precise and effective treatment of esophageal cancer.