Catalytic modulation of the tumor microenvironment using cascade enzymes for synergistic boron neutron capture therapy in the treatment of gliomas

Glioma is the most common primary malignant tumor of the central nervous system. Despite traditional treatments such as surgical resection, combined postoperative chemotherapy, and radiotherapy, it remains challenging to significantly improve the long-term survival rate of patients. This is primarily due to the incomplete surgical removal of the tumor and its resistance to radiotherapy. Boron neutron capture therapy (BNCT) is a novel radiotherapy that can selectively kill tumor cells. Current research has demonstrated that BNCT offers effective local disease control for gliomas and head and neck tumors. However, the existing boron-containing drugs are still unsatisfactory due to their low boron content and poor targeting ability. The synergistic treatment has provided new ideas for the development of BNCT, and the emergence of nanosystems offers the possibility of prolonged retention and pinpoint delivery of boron drugs in the tumor. The unique tumor microenvironment (TME) of gliomas, characterized by the blood brain barrier (BBB), oxidative stress, hypoxia and angiogenesis, renders conventional treatments ineffective and poor prognosis. Therefore, to combine the TME regulation and BNCT, we prepared a stable nanosystem in this study. It is a borane-contained cationic liposome modified with cRGD (Cyclo(Arg-Gly-Asp-d-Phe-Lys)) peptide which enhances the tumor-targeting ability. And the enzymes lactate oxidase (LOX) and catalase (CAT) are absorbed on the surface of the nanosystem which reduce the concentration of lactic acid through a cascade reaction to generate O₂ and decrease the protein expression level of hypoxia-inducible factor 1α (HIF-1α). This nanosystem exhibited a more potent anti-tumor effect both in vitro and in vivo. Also it reduced tumor stemness in vivo, which improves the prognosis. Therefore, the novel nanosystem combined microenvironment regulation therapy and BNCT shows the great potential application in anti-tumor treatment.