AM(IF=32) Tian Huayu's team at the Chinese Academy of Sciences has developed biomineralized dual-enzyme nanoparticles to achieve apoptosis of tumor cells and anti-tumor immunotherapy through glucose metabolism

iNature

At present, immune checkpoint therapy combined with chemotherapy and radiotherapy is an effective strategy
to improve the efficacy of immunotherapy.
However, chemotherapy and radiation therapy cause serious side effects, so finding safe and effective ways to combine with immunotherapy is critical
.

On October 4, 2022, the team of Tian Huayu of the Changchun Institute of Applied Chemistry of the Chinese Academy of Sciences/University of Science and Technology of China/Xiamen University published online in Advanced Materials (IF=32) titled "Biomineralized Two-Enzyme Nanoparticles Regulated Tumor Glycometabolism Inducing Tumor Cell.
" Pyroptosis and Robust Anti-Tumor Immunotherapy" research paper
.
The study found that regulating tumor glucose metabolism can induce apoptosis of tumor cells and regulate the degree
of expression of programmed death-ligand 1 (PD-L1).
Therefore, the study looked at how to treat tumors by modulating tumor glucose metabolism combined with anti-PD-L1 therapy
.

First, by using the method of biomineralization, nanoparticles
with double enzyme activity are constructed by hybridization of nanoenzymes and glucose oxidase (GOx).
It has the ability to self-amplify and regulate the glycolysis activity of tumor cells, and can also induce apoptosis of tumor cells and increase the expression
of PD-L1 in tumor cells.
To treat tumors, studies further bind nanoparticles to anti-PD-L1, which greatly inhibited tumor development and significantly increased mouse survival time
.
Combination therapy also has a significant immunomemory effect, successfully preventing tumor recurrence and metastasis
.
This is the first research to combine tumor glucose metabolism with immune checkpoints in cancer treatment, and this innovative, safe, low-toxic, and highly effective anti-tumor strategy will have good clinical application prospects
.

In recent years, tumor immunotherapy has developed rapidly
.
To fight tumors, it activates the immune system and produces a long-lasting anti-tumor immune response
.
However, the response rate of tumor immunotherapy is poor and needs to be further improved
.
For example, in most tumors such as breast cancer, the response rate of tumor immunotherapy represented by immune checkpoint therapy is less than 20%.

Therefore, tumor immunotherapy in combination with chemotherapy or radiotherapy is often used in preclinical trial studies
of tumor therapy.
But the damage to the body from chemotherapy or radiation therapy is very serious, so low-toxicity treatments used in combination with immunotherapy are crucial
.
Studies have shown that treating tumors by regulating metabolism is a therapy
with few side effects and significant efficacy.
Glycolysis is the main form
of tumor glucose metabolism.
Programmed death ligand 1 (PD-L1), as a representative of immune checkpoint therapy, is associated
with glycolysis activity.
Consuming glucose to increase tumor glycolytic activity allows tumor cells to express more PD-L1, thereby promoting anti-PD-L1 immunotherapy
.
Blocking PD-L1 can inhibit tumor glycolysis activity and enhance the ability of
T cells.
Therefore, modulating tumor glucose metabolism combined with immune checkpoint therapy can synergistically anti-tumor and produce a robust therapeutic effect
.
Glucose oxidase (GOx) catalyzes the conversion of glucose to gluconic acid and_H2O2,and can therefore be used to regulate glucose metabolism
at tumor sites.
However, the above catalytic reaction requires the participation of_O2, and the hypoxic environment at the tumor site is not conducive to the progress of
the reaction.
If you can combine catalase and glucose oxidase, you can solve the problem
very well.
Among them, catalase can catalyze_H2O2to produce_O2, which is conducive to GOx catalyzing the reaction of
glucose.
Building a fusion enzyme with dual enzymatic activity may be a viable solution
.
However, building fusion enzymes using genetic engineering often requires a tedious process
.
Therefore, it is very attractive to create a new way to build fusion enzymes
.
Scheme for GOx-Mn/HA synthesis and biomineralization of double-enzyme nanoparticles (from Advanced Materials) It is reported that biomineralization is a method
for constructing multifunctional nanoparticles with catalytic properties.
For example, the team has constructed highly efficient nanovaccines by biomineralization methods, using ovalbumin as an antigen and manganese-based nanoparticles as carriers and adjuvants to activate the cGAS-STING pathway ^[1].

Wang et al.
^[2] developed a new nanovaccine through biomineralization that contains the receptor-binding domain of spike proteins and manganese nanoadjuvants to activate the cGAS-STING pathway, thereby inducing humoral and cellular responses
.
Chen et al.
^[3] reports a novel biomineralization-inspired strategy for the synthesis of fructose-doped manganese phosphate nanoplatforms that generate high levels of reactive oxygen species through the^Mn2+-driven Fenton reaction for catalytic treatment of osteosarcoma
.
The study used a biomineral-like method to construct GOx-Mn nanoparticles with dual enzyme activity by hybridizing nanoenzymes and GOx
.
On the one hand, manganese-containing nanoenzymes catalyze the generation of_{H2O2at the tumor} site
.
On the other hand, the production of O2 can promote the glucose consumption capacity of GOx in nanoparticles and effectively regulate the glucose metabolism at the tumor site, and the_H2O2produced by it is also conducive to the catalytic reaction of nanoenzymes
.
The fusion of nanoenzymes with GOx enables the tandem of two catalytic reactions, with the ability to
circulate amplification of glucose consumption.
Surprisingly, consuming glucose in tumor cells can induce cell scorching death and trigger a strong tumor immune response
.
In addition, the depletion of glucose can cause tumor cells to express more PD-L1, which then enhances immune checkpoint blocking therapy
for PD-L1/PD-1.
GOx-Mn is then combined with hyaluronic acid (HA) to produce GOx-Mn/HA and targeted delivery in breast cancer mice by intravenous administration
.
For highly effective anti-tumor immunotherapy, Mn-GOx/HA and anti-PD-L1 are used
in combination.
According to the authors' investigation, this is the first study
to hybridize nanoenzymes and GOx by a method similar to biomineralization.
Regulating tumor glucose metabolism through immunotherapy can effectively inhibit tumor growth, recurrence and metastasis
.
The combination therapy proposed in this study is a promising anti-tumor strategy and has certain guiding significance
for clinical immunotherapy.

References:[1] S.
Zhang, Y.
Feng, M.
Meng, Z.
Li, H.
Li, L.
Lin, C.
Xu, J.
Chen, K.
Hao, Z.
Tang, H.
Tian, X.
Chen, Biomaterials2022, 289, 121794.
[2] Y.
Wang, Y.
Xie, J.
Luo, M.
Guo, X.
Hu, X.
Chen, Z.
Chen, X.
Lu, L.
Mao, K.
Zhang, L.
Wei, Y.
Ma, R.
Wang, J.
Zhou, C.
He, Y.
Zhang, Y.
Zhang, S.
Chen, L.
Shen, Y.
Chen, N.
Qiu, Y.
Liu, Y.
Cui, G.
Liao, Y.
Liu, C.
Chen, NanoToday2021, 38, 101139.
C.
Zhang, J.
Hu, Y.
Jiang, S.
Tan, K.
Zhu, C.
Xue, Y.
Dai, F.
Chen, Nanoscale2022, 14, 898 https://onlinelibrary.
wiley.
com/doi/10.
1002/adma.
202206851

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