The following are the main research directions of the research group:

1. Tumor diagnosis and treatment

2. Drug Delivery

3. Gene therapy



The following is a summary of some of the results published by Zhang Xianzhengs team in 2020 according to six parts, for everyone to learn and communicate.

Part 1. Biomimetic materials and metabolic therapy

Part 2. Immunotherapy

Part 3. Light therapy

Part 4. Drug Delivery

Part 5. Gas Therapy

Part 5. Other



1. Biomimetic materials and metabolic therapy



1. Nature Biomed. Eng.: Oral microbial cocktail, cascade system to remove waste, do you need a dialysis machine in the future?

Professor Zhang Xianzhengs research team reported on the design of an oral microbiome microecosystem that degrades intestinal nitrogen-containing wastes, showing that a bacterial cocktail taken orally in kidney-injured animals can be metabolized before blood nitrogen wastes diffuse through the intestinal mucosal barrier . Related results were published on Nature Biomedical Engineering on July 6.

Research ideas

1) First, a synthetic microbial community that converts metabolic waste into nutrients is established. Microorganisms have the potential to metabolize various nitrogenous waste products. The researchers chose to convert urea (Escherichia strain 1) or creatinine (Bacillus strain 2) into ammonia, considering the high toxicity of ammonia, plus Enterobacter that can convert ammonia into amino acids Strain (strain 3).


2) Then, through the microfluidic technology, the three kinds of bacteria are wrapped in calcium alginate microspheres to achieve spatial co-localization. This artificial ecosystem can promote the metabolic cascade between different strains.


3) A layer of polydopamine (PDA) nano-membrane is polymerized in situ on the surface of the microspheres to selectively allow small molecular nitrogen sources to enter the bacterial micro-ecosystem (BME) to prevent nitrogen-containing macromolecules Excessive consumption. The coating also improves the degradation rate of nitrogen-containing waste in complex environments. And it is assumed that oral BME can effectively remove metabolic waste without causing obvious adverse reactions.





Schematic diagram

In summary, the researchers comprehensively studied the efficacy of BME in removing metabolic waste. The encapsulated microbial mixture significantly reduces the concentration of urea and creatinine in the blood without causing any adverse effects.


Bacteria have a variety of metabolic pathways. After further strain screening, the types of waste that can be degraded by artificial flora can be further expanded. At the same time, protective probiotics can also be added to BME to eliminate metabolic waste while reducing kidney damage. According to the characteristics of different types of renal failure, bacteria with different metabolic properties and functions can be combined to achieve personalized treatment. This strategy can be developed into a technique that works synergistically with dialysis and reduces the frequency and time of dialysis.


However, the specific treatment mechanism and safety still have some problems that need to be further studied and resolved. Most importantly, with the high controllability and intelligent response of synthetic materials, there is still a lot of room to update current microbiome-based therapies to treat metabolic diseases other than renal failure.


references:

Zheng,D., et al. An orally delivered microbial cocktail for the removal of nitrogenous metabolic waste in animal models of kidney failure. Nat Biomed Eng(2020).

https://doi.org/10.1038/s41551-020-0582-1



2. Angew: Intervene in tumor development by coupling bacterial respiration and tumor metabolism

Professor Zhang Xianzheng of Wuhan University used the characteristic that Shewanella MR-1 (S. oneidensis MR-1) can decompose lactic acid anaerobicly by transferring electrons to metal minerals to carry out respiration, and the manganese dioxide (MnO2) ) Nanoflowers were modified on the surface of S. oneidensis MR-1 to construct a biological hybrid material (Bac@MnO2) that uses lactic acid as fuel.


Key points of this article:

1) The MnO2 nanoflower in Bac@MnO2 can be used as an electron acceptor, and the tumor metabolite lactic acid can be used as an electron donor, thereby establishing a complete bacterial respiratory pathway at the tumor site, resulting in continuous consumption and decomposition of lactic acid between cells.

2) In addition, the modified MnO2 nanoflowers can also catalyze endogenous hydrogen peroxide (H2O2) to generate oxygen (O2), which can further inhibit the production of lactic acid by down-regulating the expression of hypoxia inducible factor-1 (HIF-1) . Since lactic acid plays a key role in tumorigenesis, the biological hybrid material Bac@MnO2 can significantly interfere with tumor development by coupling bacterial respiration with tumor metabolism.



Qi-Wen Chen. et al. Intervening Tumor Progression by Coupling Bacteria Respiration with Tumor Metabolism. Angewandte Chemie International Edition. 2020

DOI: 10.1002/anie.202002649

https://onlinelibrary.wiley.com/doi/10.1002/anie.202002649



3. AM: Probiotic spores wrapped in prebiotics can regulate the intestinal flora and inhibit colon cancer

Although microbial-based therapy is considered an effective strategy for the treatment of diseases such as colon cancer, its safety remains the biggest challenge. In this regard, Professor Zhang Xianzheng of Wuhan University and others have used probiotics and prebiotics with ideal biocompatibility (which have been widely used as additives for food and medicine), and combined them to form a safe microbial regulation material.


Key points of this article:

1) Through the host-guest chemical reaction between commercial Clostridium butyricum and chemically modified prebiotic dextran, prebiotic-encapsulated probiotic spores (spore-dex) were prepared. Researchers found that spore-dex can specifically enrich colon cancer after oral administration. In the lesion, glucan is fermented by Clostridium butyricum to produce anti-cancer short-chain fatty acids (SCFA).

2) In addition, spore-dex regulates the intestinal flora, increases the abundance of SCFA-producing bacteria (such as eubacteria and rose fungi), and significantly increases the overall abundance of the flora. In subcutaneous and orthotopic tumor models, drug-loaded spore-dex inhibited tumor growth by 89% and 65%, respectively. Importantly, no obvious adverse effects were found. This work reveals the possibility of using highly safe strategies to regulate the intestinal flora and provides a promising approach for the treatment of various gastrointestinal diseases.



Zheng, D.‐W., et al., Prebiotics‐Encapsulated Probiotic Spores Regulate Gut Microbiota and Suppress Colon Cancer. Adv. Mater. 2020, 2004529.

https://doi.org/10.1002/adma.202004529

4. Nature Commun.: Soldiers are broken! Artificial ECM to round up solid tumors!

As one of the most important non-cellular components in the tumor microenvironment, ECM is essential to meet the needs of cancer cells to maintain rapid growth and continuous proliferation. It is reported that changes in the ECM structure will cause a restrictive metabolic reaction. So, can chemical reactions be induced in the ECM to cut off the nutrient supply and improve tumor perfusion at the same time?



In view of this, inspired by the coagulation process, the research group of Professor Zhang Xianzheng of Wuhan University reported on a coagulation system based on fibrinogen and thrombin to construct an artificial ECM (aECM) for selectively cutting off tumor metabolic flux. Once the microwound is induced, the cascade gelation of aECM can be triggered to siege the tumor. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasound therapy, surgery, or radiation therapy, which means that this strategy may be transformed into a clinical combination therapy.



the whole idea

This research group mainly uses two FDA-approved drugs (fibrinogen and prothrombin), in which fibrinogen is modified with azido (Fb-N3), and prothrombin is azodibenzocyclooctyne ( DBCO) grafting (Ptb-DBCO).

First, after Fb-N3 is injected into the tail vein, the micro wounds formed by surgery, RT or ultrasound (US) treatment trigger the specific accumulation of Fb-N3 at the tumor.

Then, Ptb-DBCO was injected again, and the bio-orthogonal reaction between DBCO and N3 group was used to make Ptb-DBCO accumulate at the tumor. Due to changes in the structure of blood vessels, Ptb can easily be converted into thrombin and the clotting process occurs. The formation of reticular blood clots surround the tumor, producing aECM fibrin gel, which is used to block nutrient exchange and prevent tumor cell migration.

Figure | In vitro gelation of aECM

summary:

In summary, this research has developed an enzymatic response-based solid tumor trapping therapy. Combined with US, surgery or RT, successfully induced aECM gelation in a variety of cancer types. This ability also establishes the advantages of introducing aECM gel into standard treatment regimens for the first-line treatment of most cancer cases. Although this enzymatic reaction-based therapy is still in its infancy, researchers believe that this strategy will provide a new way to update current cancer therapies and benefit personalized medicine.



references:

Zheng, D., et al. Controllable gelation of artificial extracellular matrix for altering mass transport and improving cancer therapies. Nat Commun 11, 4907 (2020).

https://doi.org/10.1038/s41467-020-18493-7



5. Chem. Soc. Rev: Cell primordium biomimetic functional materials for enhancing cancer treatment

Professor Zhang Xianzheng from Wuhan University reviewed the research of cell primordium biomimetic functional materials in enhancing cancer treatment.


Key points of this article:

1) Cell primordium functional materials combine the advantages of natural substances and nanotechnology, and have become an attractive cancer treatment drug. The cytoplasma has unique biological functions, such as long-term circulation in the body, tumor-specific targeting and immune regulation. In addition, synthetic nanomaterials with unique physical and chemical properties have also been widely used as drug carriers or anti-cancer agents for the treatment of cancer. Therefore, the combination of these two materials is expected to produce biomaterials with multiple functions and high biocompatibility, which can then achieve precise cancer treatment.

2) This article summarizes the research progress of materials with tumor treatment functions based on cell primordia in recent years; introduces different cell protozoa, including bacteria, phages, cells, cell membranes and other biologically active substances. Activity and function; at the same time, the author also discussed the strategy of combining it with synthetic materials, especially nanosystems to construct functionalized biological materials; finally, the author also looked forward to future research directions in this field.



Guo-Feng Luo. et al. Cell primitive-based biomimetic functional materials for enhanced cancer therapy. Chemical Society Reviews. 2020

DOI: 10.1039/d0cs00152j

https://pubs.rsc.org/en/content/articlelanding/2020/cs/d0cs00152j#!divAbstract

2. Immunotherapy



6. Nature Commun.: A vaccine-based nanosystem for improving tumor immunotherapy

The response rate of immune checkpoint block (ICB) immunotherapy is not ideal, which severely limits its clinical application as a tumor treatment. Here, Zhang Xianzheng of Wuhan University and others created a vaccine-based nanosystem by integrating Cd274 siRNA into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein.


Key points of this article:

1) The nano system has good biological safety and improves the efficacy of anti-tumor immunotherapy.

2) HPV16 L1 protein activates innate immunity through type I interferon pathway, and shows effective anti-cancer effects when combined with ICB.

3) For resectable and unresectable breast tumors, the nanosystem reduced tumor recurrence by 71% and prolonged progression-free survival by 67%.

4) The most important thing is that the nanosystem is used in various transgenes with different antigen loads.
A high response rate was successfully induced in the breast cancer model. This powerful immune stimulation stimulated by vaccine-based nanosystems may be a way to significantly improve current ICB immunotherapy.






Di-Wei Zheng, et al. A vaccine-based nanosystem for initiating innate immunity and improving tumor immunotherapy, Nat. Commun., 2020.

DOI: 10.1038/s41467-020-15927-0

https://doi.org/10.1038/s41467-020-15927-0

7. Science Advances: Bio-inorganic hybrid phage can regulate the intestinal flora to reshape the tumor immune microenvironment against colorectal cancer

More and more evidences show that the intestinal flora contributes to the tumorigenesis of colorectal cancer (CRC), in which the symbiotic Clostridium nucleoside (Fn) selectively increases immunosuppressive myeloid-derived suppressor cells (MDSC) ) To hinder the host’s anti-cancer immune response. Hereby, Professor Zhang Xianzheng of Wuhan University and others screened a specific Fn-binding M13 phage through phage display technology. Then, silver nanoparticles (AgNP) were electrostatically assembled on the surface capsid protein (M13@Ag) to achieve the specific clearance of Fn and reshape the immune tumor microenvironment.


Key points of this article:

1) Both in vitro and in vivo studies have shown that M13@Ag treatment can clear intestinal Fn and reduce the expansion of MDSC at the tumor site.

2) In addition, antigen presenting cells (APC) are activated by M13 phage to further awaken the host immune system to suppress CRC. The combination of M13@Ag and immune checkpoint inhibitor (α-PD1) or chemotherapeutic agent (FOLFIRI) can significantly prolong the overall survival time of orthotopic CRC model mice.






Dong X, et al. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Science Advances. 2020;6(20):eaba1590.

https://advances.sciencemag.org/content/6/20/eaba1590



8. AFM: NIR-triggered cascade anti-tumor immune response based on integrated core-shell nanoparticles

At present, the clinical application of anti-tumor immunotherapy is still facing severe challenges related to efficacy. Here, Zhang Xianzheng of Wuhan University and others have designed a light-triggered core-shell nanosystem to enhance anti-tumor immune response by controlling the release of anti-PD-L1 (αPD-L1) antibodies and enhancing antigen presentation.


Key points of this article:

1) Using gold nanorods (Au NRs) as the photothermal core and zeolite imidazole framework-8 (ZIF-8) as the shell for αPD-L1 delivery, and further PEGylation to construct a nanosystem--AZ-P@ P.

2) In this nanosystem, the ZIF-8 shell protects the αPD-L1 antibody from the complex physiological environment and high temperature. Once gathered at the tumor site, AZ-P@P induces tumor cell death under near infrared (NIR) light-triggered heating, and releases tumor-derived protein antigens (TDPAs) and adenosine triphosphate (ATP). After that, the released ATP degrades the ZIF-8 shell, exposing Au NRs, and promotes the infiltration of T cells in the tumor by capturing and transporting TDPA to dendritic cells (DC). At the same time, a large amount of αPD-L1 is released in situ to restore T cell activity.

3) Mechanism studies have shown that AZ-P@P can promote the maturation of DC and the infiltration of activated T cells, thereby inducing strong anti-tumor immunity. Studies have shown that AZ-P@P triggered by near-infrared light can significantly destroy the primary tumor and inhibit metastasis.

In summary, this multiple immunomodulatory system provides a promising tool for tumor treatment.

Qian Cheng, et al. Near‐Infrared Triggered Cascade of Antitumor Immune Responses Based on the Integrated Core–Shell Nanoparticle. Adv. Funct. Mater., 2020.

DOI: 10.1002/adfm.202000335

https://doi.org/10.1002/adfm.202000335



Three, light therapy



9. Biomaterials: Functional COF is used to reconstruct extracellular matrix to enhance tumor photodynamic therapy

Photodynamic therapy is a promising tumor treatment method. However, the hypoxic microenvironment of most solid tumors hinders the efficacy of PDT. Zeng Xuan and Professor Zhang Xianzheng of Wuhan University have jointly prepared a functional covalent organic framework (COF) structure, which can improve the efficacy of PDT by remodeling the tumor extracellular matrix (ECM). In the experiment, the anti-fibrotic drug pirfenidone (PFD) was loaded into the imine-based COF (COFTTA-DHTA), and modified with PLGA-PEG to obtain PFD@COFTTA- DHTA@PLGA-PEG ( PCPP). After being injected intravenously, PCPP can accumulate and release PFD at the tumor site, so that the levels of HA and collagen I of ECM are down-regulated, thereby effectively improving the tumors hypoxic microenvironment. In addition, the tumor ECM remodeling mediated by PCPP can also enhance the tumor uptake effect of protoporphyrin IX (PPIX)-conjugated peptide nanoparticles (NM-PPIX) subsequently injected, and greatly enhance the effect of tumor PDT effect.



Shi-Bo Wang, Xuan Zeng, Xian-Zheng Zhang. et al. Remodeling extracellular matrix based on functional covalent organic framework to enhance tumor photodynamic therapy. Biomaterials. 2020

https://www.sciencedirect.com/science/article/pii/S0142961220300181

10. Biomaterials: AgNPs/porphyrin MOF nano system synergistic metal ion therapy and photodynamic therapy

Metal-based therapeutics have been extensively studied for disease treatment, but still face challenges such as off-target and acute toxicity, and precise control of the release of metal ions has become an urgent problem to be solved. Recently, the research group of Professor Zhang Xianzheng of Wuhan University designed a nano-system (PAM) that uses near-infrared (NIR)-induced photodynamic therapy (PDT) to control oxidation conditions to activate and release metal ions on demand. It is used in anti-tumor and Antibacterial field.



Highlights of this article

1) Researchers modified silver nanoparticles (AgNPs) onto the porphyrin porous coordination network (PCN), and further modified them with neutrophil membrane (NM) with inflammation targeting ability to construct PAM.

2) PAM is in an inactive state without irradiation and will not cause damage to normal tissues; however, when the tumor or infected tissue is irradiated with near-infrared radiation, PCN will locally produce singlet oxygen (1O2), which makes AgNPs Partially degrade to release cytotoxic Ag+ for metal ion therapy (MIT). The light-controlled activation and release of Ag+ make the nanosystem biologically inert during the cycle, and the toxicity can be restored in a controllable manner, ingeniously avoiding the inevitable leakage problem in the current metal ion entrapment process.

3) Due to the local electric field effect, the doped AgNPs can increase the efficiency of PCN to produce 1O2. Therefore, in the presence of near-infrared light, the synergistic interaction between AgNPs-assisted enhanced photodynamic therapy and 1O2 activated metal ion therapy enables PAM to show excellent anti-tumor and antibacterial abilities both in vivo and in vitro, and there is no obvious side effect.


In summary, the AgNPs/porphyrin MOF nanosystem designed in this research can synergistically utilize metal ion therapy and photodynamic therapy to eliminate tumors and pathogens. This near-infrared-induced nanocomposite provides a meaningful reference for the design of more biomaterials that are safe, controllable and effective in treating diseases.



Lu Zhang et al. Near infrared light-triggered metal ion and photodynamic therapy based on AgNPs/porphyrinic MOFs for tumors and pathogens elimination. Biomaterials. 2020.

https://doi.org/10.1016/j.biomaterials.2020.120029