Tumor Intracellular-Environment Responsive Materials Shielded Nano-Complexes for Highly Efficient Light-Triggered Gene Delivery without Cargo Gene Damage

Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochemical internalization (PCI) has provided the opportunity to overcome endo‐lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo‐oxidation of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light‐triggered gene delivery system is demonstrated based on endo‐lysosomal pH‐responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo‐lysosomal pH‐sensitive de‐shielding ability of the pH‐responsive shielding material incorporated in the ternary gene complexes (pH‐TCs), a more significant photo‐triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH‐insensitive material‐shielded nanocarriers cause photo‐oxidation of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light‐triggered gene delivery system using pH‐TCs is applied to deliver the therapeutic p53 gene in melanoma K‐1735 bearing mice, showing excellent therapeutic potential for cancer. A new type of stable light‐triggered gene delivery system is designed based on a pH‐responsive shielding material incorporated into ternary gene complexes (pH‐TCs). The endosomal pH‐sensitive de‐shielding effect of pH‐TCs exhibits highly discriminating light‐triggered gene expression both in vitro and in vivo without cargo gene damage.