Lei Ma,Zhiying Liu,Zhijian Kong,Mengmeng Wang,Tuo Li,Han Zhu,Qun Wan,Dongyang Liu,Qirong Shen
Lytic polysaccharide monooxygenases (LPMOs) are attracting much attention for their potential application in biodegradation. However, there are limited studies on the characterization of the AA11 family. Here, a novel AA11 family protein, Tg AA11, from Trichoderma guizhouense NJAU 4742 was characterized, and the isothermal titration calorimetry (ITC) analysis results showed that it exhibited tight binding capacity for copper ions with a K d value of 4.83 ± 0.79 μM. The MALDI-TOF-MS analysis results indicated that Tg AA11 could act on β-chitin to form C1 oxidation products, and some deacetylated chitooligosaccharides. In addition, the degradation of α-chitin and β-chitin by a chitinolytic enzyme Sg -chi was substantially increased in the presence of Tg AA11 by 39.9 % and 288.2 %, respectively. Furthermore, the active site residues predicted showed that His61 and Tyr142 might be critical for the active site residues of the Tg AA11 protein. This study will contribute to the understanding of the function of AA11 LPMOs in the degradation of chitin.
Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis. The Cu-MOF is employed as nanocarrier to support siRNA with high loading efficiency, and its pH sensitivity facilitates endosomal disruption upon cellular uptake. Furthermore, the cell membrane coating Cu-MOF presents a good biocompatibility, high BBB transcytosis, and specific uptake by tumor cells within the brain. In vitro and in vivo trials have shown that TP-M−Cu−MOF/siATP7a exhibited high silencing efficiency against target gene, specifically blocked copper trafficking, increased copper intake, triggered cuproptosis, and improved therapeutic efficacy in SCLC brain metastasis tumor-bearing mice. Overall, the biomimetic nanodelivery platform presented here further offers a promising way of orchestrating gene therapy to target copper-dependent signalling for reprogramming copper metabolism and cuproptosis-based synergistic therapy in mice bearing brain metastases.
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