【Scientific Research News】College of Life Science and Technology/National Center for Nanoengineering-Professor Yang Xiangliang and Associate Professor Zhang Yan's team in protein...

Professor Yang Xiangliang and Associate Professor Zhang Yan from the School of Life Science and Technology, Huazhong University of Science and Technology have made new progress
in protease-activated nanozymes for photoacoustic/magnetic resonance-guided combination therapy of tumor ferrozois-photothermal therapy 。 The related research results were published in Advanced Functional in a research paper entitled "Protease-Activatable Nanozyme with Photoacoustic and Tumor-Enhanced Magnetic Resonance Imaging for Photothermal Ferroptosis Cancer Therapy" Materials
。

Ferroptosis is a programmed death modality
of iron-dependent cells.
The main mechanism of ferrozois is the production of excess hydroxyl radicals (· OH), catalyzes the highly expressed unsaturated fatty acids on the cell membrane, and lipid peroxidation occurs, thereby inducing cellular iron death; It is also manifested by depletion of glutathione and decreased
glutathione peroxidase (GPX4) activity.
The development of highly effective iron-dead induction drugs is one of the effective ways of
anti-tumor treatment.
However, at present, iron-dead induction drugs have shortcomings such as high systemic distribution of drugs after systematic administration, high toxicity, and limited tumor cell killing effect
.
In view of the above problems, the research team chose to use gelatin as a template, prepared Fe3O4 nanoclusters by metal coordination, combined with defective Cu1.
77Se, and developed metalloproteinase-activated Fe3O4@Cu1.
77Se nanoenzymes
.

Compared with other nanozymes, the nanozyme can maintain stable structure and performance in the physiological environment; In the presence of matrix metalloproteinases, Fe3O4@Cu1.
77Se can rapidly depolymerize, releasing ultranumerous, ultra-small Fe3O4 and Cu1.
77Se nanoparticles, which not only causes nanozyme NMR T2 signal enhancement, but also improves the efficiency of the (quasi)Fenton reaction of Fe3O4@Cu1.
77Se and enhances its hydroxyl radicals (· OH) Generation and GSH consumption efficiency
.
At the same time, Cu1.
77Se has good photothermal conversion efficiency in the near-infrared II region, which can not only produce good photothermal effects when irradiated at 1064 nm, but also further enhance the nanoenzyme Fenton reaction and GSH consumption efficiency, and achieve the synergistic effect
of 1+1>2.

After intravenous administration, under the guidance of an exogenous magnetic field, Fe3O4@Cu1.
77Se nanoenzyme can be efficiently enriched
in tumor tissue.
In tumor tissues rich in matrix metalloproteinases and exogenous 1064 nm light sources, Fe3O4@Cu1.
77Se nanoenzymes can not only effectively enhance the lipid peroxidation of tumor cell membranes, significantly enhance the process of iron death in tumor cells, but also produce photothermal effects to achieve the synergistic anti-tumor therapeutic effect
of 1+1>2 。 The treatment process effectively induces the immunogenic death of tumor cells, activates dendritic cell maturation, leads to the infiltration of toxic T lymphocytes, and causes reverse polarization of tumor-associated macrophages, thereby activating the immune response and effectively inhibiting the growth of proximal and distal tumors and lung metastasis
of tumors.

This work provides an idea for the design of tumor in situ activated hemozotic nanodrugs, and realizes synergistic and efficient anti-tumor treatment
by effectively avoiding the potential harm caused by the off-target effect of iron-dead induction drugs in the non-tumor microenvironment.

Figure 1.
Construction of protease-activated nanoenzyme _Fe3O4@Cu _1.
77 Se, evaluation of therapeutic effect and mechanism

Qin Wen and Huang Zhao, doctoral students in the School of Life Science and Technology, are the co-first authors of the paper, and Associate Professor Zhang Yan, School of Life Science and Technology, Huazhong University of Science and Technology, is the corresponding author
of the paper.
This work was supported
by the National Key Research and Development Program of China (2021YFA1201200).