Self-Generative Singlet Oxygen (¹O₂)-Initiated Chemical Modification of Nuclear DNAs Combats Tumor Drug Resistance

Multidrug resistance (MDR) is one of the major problems in cancer treatment. Overcoming MDR to achieve effective cancer treatment remains a huge challenge. Here, we proposed a self-generative singlet oxygen (¹O₂)-initiated chemical modification of nuclear DNAs (SiCMoND) approach to kill multidrug-resistant tumor synergizing with chemotherapy. A tumor-targeted "nano-bomb" FA(CT-<i>f</i>T-Dox) was rationally fabricated by encapsulating the complex of Cu²⁺ with tetrakis(4-carboxyphenyl) porphyrin) (Cu-TCPP) as a ¹O₂ generator and a doxorubicin (Dox) prodrug tailed with a furan-containing positively charged peptide (<i>f</i>TAT-Dox) within the micelles of FA-PEG₅₀₀₀-PCL₃₀₀₀ and mPEG₅₀₀₀-PCL₃₀₀₀. When FA(CT-<i>f</i>T-Dox) nanoparticles accumulated at the tumor site, they could undergo disassembly in the tumor microenvironment (TME) specifically to release Cu-TCPP and <i>f</i>TAT-Dox simultaneously. Taking advantage of the features of Cu-TCPP that can convert tumor-abundant H₂O₂ into ¹O₂ and <i>f</i>TAT-Dox that can readily penetrate the cell membrane into the nucleus, chemical modification of nuclear DNAs was realized through the covalent cyclization reaction between furan and nucleobases of nuclear DNAs under the ignition of self-generative ¹O₂, which leads to significant DNA damage and enhanced therapeutic susceptibility. More notably, the sustained release of Dox within the nucleus greatly inhibits DNA transcription and translation leading to severe cancer cell apoptosis. In vivo studies in a multidrug-resistant MCF-7/ADR tumor model showed that the antitumor efficacy of FA(CT-<i>f</i>T-Dox) was 1.6-fold higher than FA(CT-T-Dox) without DNA modification functionality with a tumor suppression efficiency of 83.3%. This SiCMoND-assisting chemotherapy strategy provides a promising antitumor therapeutic modality and opens new avenues for battling multidrug-resistant tumors.