Microneedle‐Loaded Gene‐Editable Nanohybrids Engineer Cancer Cells by Telomere Stress Induction and Metabolic Interference for Enhanced Cuproptosis and Immunotherapy

Abstract Cuproptosis, a novel copper‐driven cell death, offers potential for cancer therapy, yet challenges persist in targeted delivery of copper ions and therapeutic resistance management. Here, CuTG‐Cas9@PLL, a cuproptosis nano‐inducer for efficient delivery of Cu ions, 6‐Thio‐dG (6‐thio‐2′‐deoxyguanosine), and CRISPR/Cas9 to enhance cuproptosis and immunotherapy via telomere stress and metabolic interference is developed. This system, combined with microneedle patches for transdermal delivery in melanoma treatment, targets the “Warburg effect,” a key resistance mechanism, through CRISPR/Cas9‐mediated LDHA knockout, thereby sensitizing cancer cells to cuproptosis and reversing immune suppression. Moreover, 6‐Thio‐dG‐induced telomere stress not only amplifies cuproptosis via autophagy dysfunction but also boosts anti‐tumor immunity by increased immunogenicity of senescent cancer cells. This work presents a novel approach for developing efficient cuproptosis nano‐inducers and reports on the feasibility of enhancing cancer cuproptosis and anti‐tumor immunotherapy through telomere stress induction and CRISPR/Cas9‐mediated metabolic interference.