Photosensitizers (PSs) with effective two-photon absorption in the therapeutic window are the key to two-photon photodynamic therapy. However, the traditional exogenous PSs usually lead to rejection in the body. Besides, the precise visualization of treatments proposes new demands and challenges for the design of PSs. Accordingly, in this work, a series of quasi-intrinsic PSs are obtained based on the artificial base 2-amino-8-(1'-β-d-2'-deoxyribofuranosyl)-imidazo[1,2-α]-1,3,5-triazin-4(8H)-one (P). The calculations show that the structural modification could enhance the two-photon absorption and fluorescence emission, which is beneficial for tumor localization. Furthermore, the reduced singlet-triplet energy gaps and enhanced spin-orbit coupling contribute to the rapid intersystem crossing process, which results in a triplet state with high quantum yields. To ensure the phototherapeutic performance of the newly designed PSs, we also examined the vertical electron affinity and vertical ionization potential for generation of superoxide anions, as well as the T1 energy required to produce singlet oxygen.