O2-self-supplying and glutathione-depleting scaffold for synergistic cancer therapy

Photodynamic therapy (PDT) has great potential for tumor therapy because of its non-invasive and high selectivity. However, the therapeutic effect of PDT is critically restricted by hypoxia and glutathione (GSH) overexpression in the tumor microenvironment (TME). In this work, CeO 2 with catalase and peroxidase dual enzyme activities was loaded on Ti 3 C 2 nano-sheet, and the nanosystem was then introduced in poly-L-lactic acid (PLLA) and prepared into bone scaffold using selective laser sintering technology. Specifically, CeO 2 alleviates hypoxia through its catalase enzyme activity, which promotes the continuous photodynamic process. CeO 2 also consumes over-expressed GSH through its redox reaction and amplifies the oxidative stress in TME, thus improving the curative effect of PDT. On the other hand, the photothermal effect of scaffold can not only generate heat to kill tumor cells, but also enhance the activity of nanoenzyme, and the catalase activity enhanced by photothermal effect is fed back to PDT, forming a two-way promotion. The results indicated that the concentration of oxygen in PLLA/Ti 3 C 2 -CeO 2 scaffold group was 9.76 mg/L higher, and the concentration of singlet oxygen ( 1 O 2 ) and hydroxyl radical (·OH) was respectively increased by 60% and 170%, compared with the PLLA/Ti 3 C 2 scaffold. Moreover, the PLLA/Ti 3 C 2 -CeO 2 scaffold showed a higher GSH consumption rate, indicating that it could consume the overexpressed GSH. Therefore, the Ti 3 C 2 nano-sheet loaded with CeO 2 could combine the dual enzyme activities, photodynamic and photothermal effect to enhance the tumor therapy with a tumor growth inhibitory effect of approximately 88.8%. In summary, introducing the Ti 3 C 2 nanosystem loaded with nanozyme into PLLA scaffold is a promising strategy to develop bone scaffold with multimodal anti-tumor function. • PLLA/Ti 3 C 2 -CeO 2 scaffold was successfully synthesized. • PLLA/Ti 3 C 2 -CeO 2 scaffold can alleviate tumor hypoxia, thus improve the efficacy of O 2 -dependent PDT. • The redox reaction of PLLA/Ti 3 C 2 -CeO 2 scaffold consumes over-expressed GSH and promotes oxidative stress. • PLLA/Ti 3 C 2 -CeO 2 scaffold effectively regulates PDT/PTT/enzyme catalysis synergistic therapy for tumor by responding to tumor microenvironment.