Abstract
Background: Photodynamic therapy (PDT) has gained widespread attention in cancer treatment, but it still faces clinical problems such as skin phototoxicity. Activatable photosensitizers offer a promising approach to addressing this issue. However, several significant hurdles need to be overcome, including developing effective activation strategies and achieving the optimal balance between photodynamic effects and related side effects. Herein, we present a novel and general strategy for the construction of tumor-targeted activatable nanophotosensitizers (TNP1/PSs). Methods: TNP1/PSs were constructed through simple nanoprecipitation method, leveraging the strong cation-π interaction between cationic polymers and aromatic photosensitizers. We conducted a comprehensive characterization and investigation of the photoactivity, as well as the mechanisms underlying both OFF state and switched-on properties of TNP1/PSs. Additionally, we thoroughly evaluated the cytotoxicity, tumor-targeted ability, and anti-tumor efficacy of TNP1/PSs in the 4T1 cell line. Results: TNP1/PSs exhibit a markedly fully OFF state of photoactivity, subsequent to self-assembly through cation-π interactions in aqueous media. The mechanism study reveals a multi-pathway process induced by cation-π complexes, which includes reduced absorption and radiative decay, as well as enhanced thermal decay and intermolecular charge transfer. Upon targeting tumor cells, TNP1/PSs were effectively endocytosed and predominantly traversed the lysosomes, where degradation of the cationic polymer occurs, resulting in the spontaneous switch-on of PDT activity. In vivo studies employing small animal models demonstrated that the as-synthesized nanophotosensitizer possesses remarkable anti-tumor activity while completely avoiding skin phototoxicity. Conclusion: This work provides a powerful platform for efficiently constructing tumor-targeted activatable nanophotosensitizers, paving the way for safe and effective photodynamic therapy in cancer treatment.