Photodynamic therapy (PDT) has attracted considerable interest in recent years as an effective and promising approach for tumor treatment. In particular, the nuclear-targeted type I photosensitizers (PSs) can directly damage nuclear DNA of tumor cells, thereby significantly enhancing the therapeutic efficacy of PDT. However, the nuclear DNA-targeted PSs are rarely reported owing to the lack of clear design principles. Here, we developed a novel DNA-targeted photosensitizer (Se-PC) for highly efficient tumor PDT. After incubation with CT DNA, the fluorescence of Se-PC was dramatically enhanced, indicating its great affinity with DNA. Additionally, Se-PC exhibited strong superoxide radical (O2•⁻) generation ability under light irradiation. Due to the interaction between DNA and Se-PC, the generated O2•⁻ directly induced structural damage of DNA, ultimately leading to cell death. In vitro experiments showed that Se-PC effectivelylocated in nuclear and achieved excellent killing performance against tumor cells. Benefiting from type-I characteristics, the cell proliferation was also remarkably inhibited by the combination of Se-PC and excitation light even under severe hypoxic condition (2% O2). Furthermore, in vivo studies demonstrated that Se-PC exhibited notable efficacy in the photoablation of solid tumors, endowing Se-PC with great potential for advancing clinical translation of tumor PDT.
