## 2 Computational Details
### Quantum Mechanical Calculations  
Gaussian 16 package was used to perform all quantum mechanical calculations [28]. B3 LYP including Grimme's dispersion correction for nonbonding interactions was employed using atom pair-wise additive scheme [39], the DFT-D3 method. The 6-311G** basis set was employed to describe all the atoms. Frequency calculations were performed at the same level of theory for all located stationary points to confirm their nature of minima and transition states and for zero-point energy corrections calculations. All the located transition states were checked to be properly connected to the corresponding minima by means of intrinsic reaction coordinate (IRC) analysis [40; 41]. Full geometry optimizations, without imposing any constrain, were carried out in in implicit water (\(\varepsilon=78.4\)) using the PCM continuum solvation model as implemented in Gaussian 16 [42]. Enthalpies and Gibbs free energies were obtained at 298 K at 1 atm from total energies, including zero-point, and thermal and solvent corrections, using standard statistical procedures [43]. To accurately describe the photophysical properties, a preliminary benchmark study was carried out on both SAN and DHSAN. The optimized structure at the B3 LYP level in water implicit solvent was used to compute the excitation energies employing several functionals: B3 LYP, camb3 LYP [44], M06L [45], PBE [46], B3P86 [47], \(\omega\)B97 XD [48], and PW91 [49] including the Grimme dispersion corrections (DFT-D3). Their performances were evaluated comparing S\({}_{1}\) absorption peak wavelengths in water and THF for SANand DHSAN, respectively (Table S1). Then, B3 LYP-D3 was selected as the most suitable exchange and correlation functional, and it was used for all the TDDFT calculations. To establish whether DHSAN is able to produce \({}^{1}\)O\({}_{2}\) required to generate SAN, the possibility of an intersystem spin crossing from a bright singlet state to a triplet one of DHSAN was taken into consideration by computing the spin-orbit matrix elements, within the atomic-mean field approximation as implemented in the ORCA code [50,51] at the same level of theory used for the other calculations (PCM/B3 LYP/6-311G(d,p)). The same calculation was performed on SAN to ascertain its ability to act as photosensitizer as well. The Dalton code [52] was used to evaluate the two-photon absorption cross section that can probe the applicability of the drug as a PDT two-photon agent. For this purpose, the quadratic-response TD-DFT approach was used. B3 LYP coupled with 6-311G(d,p) were selected for such calculations that are performed in an implicit (PCM) water environment by considering the non-equilibrium contributions of the solvent to the response calculation. The representative structure of the most populated clusters was used to build up a model including the drug and the eight surrounding nucleotides for further TDDFT analysis. The intercalated SAN geometries from the extracted conformations were optimized together with the four nearby nucleobases, the rest of the atoms were kept frozen in order to avoid the unrealistic distortion of the DNA portion included in the QM calculations because of the absence of the rest of the dodecamer used for the MD intercalation study. The optimization and then the absorption spectrum in implicit solvent water was obtained maintaining B3 LYP and the 6-311G(d,p) basis set for all the atoms of SAN, 6-31G(d,p) was, instead, employed to describe the nucleobases that surround the drug and the standard 6-31G basis set for the rest of the atoms of the DNA portion. In order to ascertain the influence of the DNA on the photophysical properties, the spin-orbit matrix elements were computed as well. Nevertheless, given the size of the systems SAN-nucleobases, the computation of such property was only possible using a small basis set (6-31G) describing all the atoms. However, these quantities were preliminarily calculated for SAN with both basis set, 6-311G(d,p) and 6-31G.