Recently, the Tsinghua University team has developed an oral nanomedicine that kills two birds with one stone, which can accurately target and effectively regulate the immune microenvironment of lesions, so that ulcerative colitis can be treated quickly and safely.
（来源：Science Advances）
This not only brings hope for the development of new strategies for the treatment of ulcerative colitis, but also lays the foundation for the development of new oral drugs for gastrointestinal and immune disorders.
Previously, there were two major difficulties in the treatment of ulcerative colitis, one is the difficulty of local drug delivery, and the other is the difficulty of immune regulation of the intestinal microenvironment.
This study provides a highly effective and precise treatment plan, and this dual strategy of "killing two birds with one stone" can not only improve the treatment effect, but also reduce side effects.
For patients with ulcerative colitis, their intestinal microenvironment is high in reactive oxygen species (ROS), which can cause immune disorders.
To this end, the research group designed and synthesized a reactive oxygen species-responsive ε-polylysine and used it as a high-efficiency scavenger for reactive oxygen species.
By using the desolvation method, the team prepared a nanoparticle, and wrapped chitosan and low molecular weight heparin in the outer layer of the nanoparticle in turn through layer-by-layer (LBL) technology, so as to prepare a targeted preparation.
The team found that there is a high expression of integrin-α4 and integrin-αM on the surface of inflammatory cells. The use of heparin, which has a lower molecular weight, allows for specific targeting of these integrins.
The above findings were further confirmed by in vivo and in vivo experiments, as well as analysis combining qualitative imaging techniques with quantitative flow cytometry.
At the same time, it also found that the reactive oxygen species-sensitive bond in polylysine can quickly and effectively remove reactive oxygen species in the microenvironment, so as to achieve the effect of "killing two birds with one stone", and then can achieve effective treatment of ulcerative colitis.
This design is not only simple, but also highly adaptable, which is of great significance for the development of integrin-targeted therapy strategies for autoimmune diseases.
According to the researchers, the targeted delivery system designed this time is divided into two core modules, the reactive oxygen species scavenging module and the targeting module.
These two complement each other and can achieve the dual effect of the system targeting the site of inflammation and scavenging reactive oxygen species in situ.
In terms of application prospects, by following this modular design approach, new multifunctional targeted oral delivery systems can be developed according to the characteristics of different disease microenvironments, and then efficient targeted oral delivery systems with multiple functional components can be developed.
Furthermore, by optimizing the preparation process and selecting materials with higher biocompatibility and better biosafety, it is expected to break the dilemma of no specific drug for the clinical treatment of ulcerative colitis in a few years.
In addition, the combination of AI technology and the use of modular design ideas is expected to enable the effective development of composite functionally targeted formulations.
（来源：Science Advances）
"Killing two birds with one stone" oral nanomedicine
According to the team, ulcerative colitis (UC) is a worldwide refractory disease that cannot be completely cured and has a high risk of cancer.
Since the first case of ulcerative colitis was discovered in 1859, the incidence of ulcerative colitis has increased worldwide. As of 2016, there have been more than 10 million cases of ulcerative colitis worldwide.
At present, the clinical treatment of ulcerative colitis mainly includes drug treatment and surgical treatment.
Therapeutic drugs mainly include anti-inflammatory drugs, cortisol drugs, immunosuppressant drugs and non-steroidal compound drugs, but they have disadvantages such as large side effects, poor specificity, and poor therapeutic effect.
Surgical treatment not only brings great physical pain and economic burden to patients, but also causes irreversible damage to the patient's intestines.
Therefore, it is of great scientific, social and economic significance to develop new strategies and systems for the treatment of ulcerative colitis that are safe and effective.
Professor Xing Xinhui, Associate Professor Zhang Canyang and Assistant Professor Wang Yi of Tsinghua University are the three corresponding authors of this paper.
Xing Xinhui has been deeply involved in the field of health for many years, focusing on the research of active substance mining and green manufacturing for sub-health prevention and control and refractory disease treatment.
Zhang Canyang mainly focuses on the creation of biohybrid systems based on drug targeted delivery technology and the study of their application in disease treatment.
Wang Yi focuses on the creation of natural active polysaccharides and peptide drugs, and is good at exploring the efficacy mechanism of drugs.
Dr. Long Huang is the lead executor of this study, and his research direction is the creation of low molecular weight heparin and the development of related functions.
In a regular group meeting, Huang Long made a review report on the application of heparin in the field of biomedicine.
When referring to the targeted integrin function of heparin, the three corresponding authors realized that heparin has great potential in the targeted treatment of ulcerative colitis, and after discussion, they designed the topic of this oral delivery system for the treatment of ulcerative colitis based on heparin.
The pathogenic mechanism of ulcerative colitis is complex, and what mechanism should be used as the starting point has become the first problem encountered in research.
Through Huanglong's systematic research, combined with the research group's experience in the development of peptides and other drugs, they decided to design reactive oxygen species to remove peptides, so as to achieve the treatment of ulcerative colitis.
Once the drug was decided, a series of questions followed:
How to ensure the stability of the drug in the anterior gastrointestinal tract?
How to achieve efficient colon site targeting and drug release of the system?
What methods should be used to characterize the stability, targeting, and therapeutic efficacy mechanism of the design system?
In response to these problems, the three corresponding authors had dozens of discussions with Huang Long, and mobilized other graduate students in the team to jointly promote the project.
After more than two years of hard work, they prepared and validated the delivery system that met the expectations of the initial design.
最终，相关论文以《“一石二鸟”的口服纳米药物通过靶向肠道整合素和调节氧化还原平衡来治疗溃疡性结肠炎》（“Two-birds-one-stone”oral nanotherapeutic designed to target intestinal integrins and regulate redox homeostasis for UC treatment）为题发在 Science Advances[1]。
Corresponding authors of the paper, from left to right: Associate Professor Zhang Canyang, Professor Xing Xinhui and Assistant Professor Wang Yi (source: Zhang Canyang)
Long Huang is the first author, and Professor Xing Xinhui, Associate Professor Zhang Canyang, and Assistant Professor Wang Yi of Tsinghua University serve as co-corresponding authors.
Figure | Related papers (Source: Science Advances)
A new approach to the design of probiotic systems
According to the researchers, the modular design scheme in the above topic has brought great inspiration to another research project of the team.
As mentioned earlier, ulcerative colitis has a complex pathogenic mechanism and is still facing a lack of clinical treatment. There are still many challenges in achieving effective treatment of ulcerative colitis.
In particular: how to restructure a healthy microbiome? How to regulate immunity to achieve homeostasis? How can we reveal the correlation between the above factors?
However, oral probiotics have shown great potential in the reconstitution of intestinal microbiota and immune homeostasis in patients with ulcerative colitis.
然而，自 Mutaflor®（活性成分为益生菌 Escherichia coli Nissle 1917（EcN））问世已有 100 多年，至今仍是唯一被成功用于溃疡性结肠炎临床治疗的益生菌药物。
In addition, the efficacy of Mutaflor® is not significantly superior to that of mesalazine, the current first-line clinical drug for the treatment of ulcerative colitis. In other words, Mutaflor® does not fundamentally change the dilemma of treating ulcerative colitis without a specific cure.
The reason for this is that the mechanism of probiotics in the treatment of ulcerative colitis has not been fully understood, so there is a lack of guidance from the theoretical system, resulting in the unstable efficacy and unclear treatment mechanism of current probiotic products.
Therefore, for the clinical treatment of ulcerative colitis, there is an urgent need to develop new oral probiotic preparations to restructure the intestinal microbiota to maintain immune homeostasis, and at the same time, it is necessary to reveal its mechanism of action.
In order to solve the above problems, the research group designed an oral probiotic delivery system, using biomacromolecular materials such as lignin, which are difficult for the human body to absorb, to surface engineer the probiotics.
This not only increases the stability of probiotics in the gastrointestinal tract, but also maintains the high activity of probiotics.
Through the modified method, the team introduced pH response groups to achieve efficient release of probiotics in the colon, so as to achieve efficient colonization of probiotics in the colon.
At the same time, the team also conducted a detailed analysis of the surface engineering technology of probiotics, the physicochemical properties of the biohybrid system, the delivery mechanism and the therapeutic mechanism.
The kinetic simulation of the release of biological heterozygous system in the digestive tract and the proliferation process of probiotics was carried out by combining theory with experiments.
Through the cross-corroboration of experimental results, they established a general kinetic model of similar systems in the gastrointestinal tract, which can be used to guide the rational design of related systems.
In terms of mechanism research, they revealed the deep mechanism of the treatment of ulcerative colitis from two aspects: immune regulation and intestinal environment regulation.
Combined with molecular biology methods such as flow cytometry, confocal, and polymerase chain reaction, as well as bioinformatics analysis techniques such as 16S and metabolomics, the research group linked the two mechanisms through intestinal metabolites.
In this way, the key microflora and key metabolites that regulate immunity and repair the intestinal barrier have been discovered, and the mechanism of probiotics in the treatment of ulcerative colitis has been systematically revealed.
Thus, it provides new ideas and methods for the design of probiotic systems, the treatment of gastrointestinal diseases and immune disorders.
（来源：Science Advances）
In future research, the team will try to use AI for precision drug design and optimized delivery systems.
AI can analyze large amounts of compound data to predict and design drug molecules that can precisely target ulcerative colitis lesions.
Through machine learning and deep learning algorithms, AI can also identify biomarkers associated with the pathophysiology of ulcerative colitis to guide the development of new drugs.
In addition, through AI-assisted design, the research group will also try to develop pH-sensitive or redox-sensitive nanoparticles to release drugs in the colon-specific microenvironment.
Overall, they believe that the series of formulations designed based on the "kill two birds with one stone" design concept will show great potential in the development of oral formulations for the treatment of ulcerative colitis.
With the further integration and development of biology, materials, pharmaceuticals, chemical engineering, medicine and other disciplines, the research group expects to translate this design concept into practical treatment plans and bring more effective treatment options for patients with ulcerative colitis.
Resources:
1.https://www.science.org/doi/10.1126/sciadv.ado7438#tab-contributors
Typesetting: Luo Yi, Liu Yakun