Glutathione-Activatable and O₂/Mn²⁺-Evolving Nanocomposite for Highly Efficient and Selective Photodynamic and Gene-Silencing Dual Therapy

Photodynamic therapy (PDT) has been applied in cancer treatment by converting O₂ into reactive singlet oxygen (¹O₂) to kill cancer cells. However, the effectiveness of PDT is limited by the fact that tumor hypoxia causes an inadequate O₂ supply, and the overexpressed glutathione (GSH) in cancer cells consumes reactive oxygen species. Herein, a multifunctional hybrid system is developed for selective and highly efficient PDT as well as gene-silencing therapy using a novel GSH-activatable and O₂/Mn²⁺-evolving nanocomposite (GAOME NC). This system consists of honeycomb MnO₂ (hMnO₂) nanocarrier loaded with catalase, Ce6, and DNAzyme with folate label, which can specifically deliver payloads into cancer cells. Once endocytosed, hMnO₂ carriers are reduced by the overexpressed GSH to Mn²⁺ ions, resulting in the reduction of GSH level and disintegration of GAOME NC. The released catalases then trigger the breakdown of endogenous H₂O₂ to generate O₂, which is converted by the excited Ce6 into ¹O₂. The self-sufficiency of O₂ and consumption of GSH effectively enhance the PDT efficacy. Moreover, DNAzyme is freed for gene silencing in the presence of self-generated Mn²⁺ ions as cofactors. The rational synergy of enhanced PDT and gene-silencing therapy remarkably improve the in vitro and in vivo therapeutic efficacy of cancers.