Bacteria "camouflage" well, see me hide from the sky

Bacteria can be used both as therapeutic drugs and as drug delivery vehicles, showing great potential
in the treatment of many diseases.
But bacterial stress to the environment is often fragile, which causes bacteria to die, resulting in a decrease
in the effectiveness of treatment.
Therefore, bacterial surface modification becomes a simple and useful strategy
.
Bacterial surface modification not only gives bacteria additional resistance to environmental threats, but also gives them certain exogenous characteristics
.
This article mainly introduces the methods of bacterial surface modification, the practical application of bacterial surface modification in intestinal diseases, and the opportunities and challenges
in clinical translation.

The human body is inhabited by trillions of bacteria, some on the skin and some in the body
.
An indispensable symbiotic relationship
is formed between bacteria and the human body.
Bacteria are involved in a number of complex physiological activities, including immune regulation, digestion of food, absorption and metabolism of nutrients and drugs, and intestinal barrier function
.
Some diseases are also linked to bacteria, such as diabetes, obesity, mental diseases, autoimmune diseases, and cancer
.
The importance of bacteria to people can be
imagined.

Bacteria can do this by exerting their innate functions, such as activating immunity and secreting bacteriocins and as drugs
to treat diseases.
On the other hand, bacteria can also be used as vehicles to deliver drugs to lesions
.
However, there are still significant challenges to be solved
in bacterial therapy.
Bacteria are often affected by the environment, which leads to cell death and unsatisfactory therapeutic outcomes
.
For example, oral probiotics have been used to treat inflammatory bowel disease, but the gastrointestinal environment is complex, with pepsin and low pH in the stomach, digestive enzymes and bile acids in the intestine, etc.
, so that the gastrointestinal environment has a great negative impact on the activity of probiotics, resulting in a significant decrease
in bioavailability and therapeutic effect.
Therefore, we urgently need to adopt innovative strategies to solve these difficulties, and from this there is a bacterial surface modification strategy
.

There are three main aspects of different decoration strategies on the surface of bacteria: (1) camouflaging bacteria, reducing their immunogenicity and pathogenicity, and improving the safety of bacterial treatment without affecting their viability and proliferation ability; (2) protect bacteria, strengthen their resistance to environmental threats, and improve bacterial bioavailability or drug availability at disease sites; (3) Endow bacteria with certain exogenous functions to effectively and accurately control the activity and biological behavior of bacteria to improve the therapeutic effect
.
The following will describe the physicochemical and biological methods of bacterial surface modification:

1 Physical and chemical surface modification

The outer membrane of bacteria consists of a variety of substances, including peptidoglycans, phosphoric acids, lipopolysaccharides, lipids, and proteins
.
The surface of bacteria has various functional groups, such as sulfhydryl groups, hydroxyl groups, carboxyl groups and amino groups, etc.
, which can be surface decorated
by chemical and physical methods.
Commonly used methods include covalent coupling, in-situ polymerization, electrostatic interaction, hydrophobic interaction, etc
.
The following table shows the physical and chemical surface modification applications
of some bacteria.

2 Biological surface modification

Compared with physicochemical modification methods, biological methods have stronger biocompatibility and biosafety
for bacteria.
Physicochemical methods can modify bacteria according to the functional groups on their surface and give them a variety of exogenous properties, while biological methods can introduce persistence functions
.
Commonly used biological surface modification techniques include membrane encapsulation, ligand-receptor interaction, genetic engineering, and metabolic markers
.
The following table shows the biological surface modification applications
of some bacteria.

The intestinal flora plays an important role
in regulating the body's metabolism and maintaining homeostasis in the intestine and mucosa.
The intestinal flora participates in and even dominates food digestion, synthesis of essential vitamins, removal of pathogens, elimination of toxins and carcinogens, and maintenance of intestinal function
.
In addition, bacteria, as an important part of the intestinal defense barrier, can trigger mucosal immunity, affect intestinal permeability, regulate intestinal microbiota, and ultimately change the intestinal microbiome
.
Intestinal dysbacteriosis is associated with a variety of gastrointestinal diseases, such as intestinal barrier dysfunction, IBD, and colorectal cancer
.

Oral probiotics are the preferred method, and oral probiotics have the advantages
of simple and convenient operation and improved patient compliance.
However, strong acids in the stomach, bile acids and different enzymes in the intestine have a huge negative impact on the viability of probiotics, which greatly reduces the therapeutic effect
of oral probiotics.
So we can improve the viability and bioavailability of bacteria through surface modification of bacteria, and we can also integrate additional exogenous functions
for bacteria.
After modification, a sufficient amount of probiotics can reach the intestine and survive longer, thereby improving the therapeutic effect
.

The figure below shows two applications of bacterial surface modification in intestinal diseases: (a) the picture shows probiotic double decoration for protection, selective release, adhesion and isolation of probiotics, and enhance the prevention and treatment of colitis; (b) The picture shows yeast membrane-coated probiotics for targeted oral delivery into the Paier node, promoting mucosal immunity and regulating intestinal homeostasis
.

The use of physicochemical and biotechnology to modify the surface of bacteria has brought new hope
for biological therapeutic approaches.
It not only reduces immunogenicity, but also integrates the required exogenous functions to improve targeting capabilities and therapeutic effects
.
Genetic engineering methods can also reduce the pathogenicity
of bacteria by knocking out to hide immunogenic surfaces.

However, as an emerging research field, there are many obstacles to the clinical transformation of bacterial surface modification, including scale-up production, long-term storage, bacterial viability, gene stability, dose determination, and optimization of transport conditions
.
However, it is believed that with the development of physicochemistry and biotechnology, bacterial surface modification technology will also be further developed, which will eventually help to translate bacteria-based drugs into clinical applications
.

References

[1] Wu Feng,Liu Jinyao,Decorated bacteria and the application in drug delivery.
[J] .
Adv Drug Deliv Rev, 2022, 188: 114443.

CHEN Fuming, LI Na, XING Jiehua, et al.
Research Progress on Cell/Bacteria-Driven Drug Delivery Systems[J].
Progress in Biochemistry and Biophysics, 2019.