Hypoxia in the tumor microenvironment (TME) greatly limits the tumor-killing therapeutic efficacy of sonodynamic therapy (SDT); this phenomenon is further exacerbated by increased glutathione (GSH) levels in cancer cells. Simultaneously, cancer starvation therapy is increasingly recognized nowadays as a promising clinical translation, but the efficacy of glucose oxidase (GOx)-based starvation therapy is also limited by the lack of oxygen in the tumor. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme and can therefore be a target for starvation therapy in the absence of oxygen engagement. Here, we proposed thiol-ene click reactions based on a two-dimensional metal-organic framework (MOF) modification for tumor treatments to enable the combination of SDT and starvation therapy. Experimental studies demonstrated that the prepared material could consume GSH and GAPDH free from oxygen in TME, which benefited from the thiol-ene click reactions between the MOFs and thiol substances in cancer cells. Further experiments in vitro and in vivo indicated the prepared MOF materials could kill cancer cells efficiently. This study is expected to create a promising avenue for thiol-ene click reactions in SDT and starvation therapy for cancer.

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To develop inhibitors targeting DNA damage repair pathways is important to improve the effectiveness of chemo- and radiotherapy for cancer patients. Rad51 mediates homologous recombination (HR) repair of DNA damages. It is widely overexpressed in human cancers and overwhelms chemo- and radiotherapy-generated DNA damages through enhancing HR repair signaling, preventing damage-caused cancer cell death. Therefore, to identify inhibitors of Rad51 is important to achieve effective treatment of cancers. Transcription factor Nanog is a core regulator of embryonic stem (ES) cells for its indispensable role in stemness maintenance. In this study, we identified Nanog as a novel inhibitor of Rad51. It interacts with Rad51 and inhibits Rad51-mediated HR repair of DNA damage through its C/CD2 domain. Moreover, Rad51 inhibition can be achieved by nanoscale material- or cell-penetrating peptide (CPP)-mediated direct delivery of Nanog-C/CD2 peptides into somatic cancer cells. Furthermore, we revealed that Nanog suppresses the binding of Rad51 to single-stranded DNAs to stall the HR repair signaling. This study provides explanation for the high γH2AX level in unperturbed ES cells and early embryos, and suggests Nanog-C/CD2 as a promising drug candidate applied to Rad51-related basic research and therapeutic application studies.