GE11/RGD Dual-Ligand Copper Nanoassemblies Synchronize Cuproptosis and Photothermal Therapy for Targeted Cervical...

Cervical cancer remains a major global health burden. Conventional surgery, radiotherapy, and chemotherapy are limited by insufficient tumor targeting, severe systemic toxicity, and drug resistance, highlighting an urgent need for safe, precise, and combinatorial therapeutic strategies. In this work, we fabricated one-step self-assembled GE11/RGD dual-ligand-modified copper nanoassemblies (GR@Cu NPs). These nanoparticles display densely modified targeting peptides on a copper-rich surface and enable efficient tumor accumulation with minimal off-target distribution. Under 980 nm near-infrared irradiation (1.0 W/cm², 5 min), GR@Cu NPs trigger a photothermal-copper ion synergistic cascade. The rapid release of Cu²⁺ promotes dihydrolipoamide S-acetyltransferase oligomerization, ferredoxin 1 (FDX1) downregulation, and mitochondrial collapse, thereby initiating cuproptosis. The leaked mitochondrial DNA (mtDNA) further activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-interferon regulatory factor 3 (IRF3) pathway, reshaping the antitumor immune microenvironment. In vitro, GR@Cu NPs are rapidly and selectively internalized by HeLa and SiHa cervical cancer cells. In a HeLa xenograft nude mouse model, a single 5 min laser irradiation (1.0 W/cm², tumor temperature ∼ 51 °C) achieves potent and long-lasting tumor suppression for 21 days, without obvious body weight loss or histological damage to major organs. By integrating dual-ligand targeting with synergistic cuproptosis and photothermal therapy, this study provides an effective, low-toxicity, and precise strategy for cervical cancer treatment.