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When we hear the word "bacteria", we are more likely to associate dirty things such as sewage and rotten food in our subconscious mind
.
But in fact, there are billions of symbiotic flora in our body, these microorganisms play an important role in human health, and even affect our physique, personality and thinking
This has also inspired scientists to develop "living bacterial therapeutics", where microorganisms can be engineered into intelligent life medicines that sense and respond to their environment, and they can colonize the gastrointestinal tract, mouth, skin, lungs and tumors, And provide treatment in the local microenvironment
.
Unfortunately, while live bacterial therapy is a new, alternative approach to treating many types of cancer, there are still many hurdles to overcome, such as being judged by the body's immune system as a foreign invader, which can induce a high inflammatory response
.
Recently, researchers from Columbia University in the United States published a research paper entitled: A programmable encapsulation system improves delivery of therapeutic bacteria in mice in the journal Nature Biotechnology .
Research paper on Nature Biotechnology A programmable encapsulation system improves delivery of therapeutic bacteria in mice.
A programmable encapsulation system improves delivery of therapeutic bacteria in mice
This study develops a genetically encoded microbial encapsulation system whose regulated and dynamic expression of surface capsular polysaccharides enhances systemic delivery, allowing therapeutic bacteria to hide from the immune system
.
In mouse tumor models, the novel camouflage system successfully delivered live bacterial drugs to tumors and killed cancer cells in vivo
Live bacterial therapy has been proposed as an alternative to treat a variety of cancers, but its host toxicity has also limited tolerable doses and efficacy, and in some cases has led to the termination of clinical trials
.
Furthermore, unlike traditional drug carriers, bacteria are dynamic—they reproduce and migrate constantly, requiring strong temporal control of their in vivo pharmacokinetics
One approach to circumvent the immunogenicity and toxicity of live bacterial treatment is to knock out antigens on the bacterial surface, such as lipopolysaccharide (LPS), but this strategy also suffers from strain attenuation and reduced colonization
.
So what if we changed our minds and instead of knocking out these antigenic molecules, we concealed them?
Therefore, another alternative strategy is to coat microbial surfaces with molecular coatings, such as alginate, chitosan, polydopamine, lipids, and nanoparticles
.
But these one-time, static bacterial modifications do not allow for in situ modulation and can lead to uncontrolled growth, off-target histotoxicity or impair cellular function, thereby reducing therapeutic efficacy
In conclusion, how to improve the efficiency of bacterial delivery without compromising safety is the core challenge for realizing live bacterial therapy in the clinical treatment of cancer
.
.
How to improve the efficiency of bacterial delivery without compromising safety is a core challenge in realizing live bacterial therapy in the clinical treatment of cancer
Programmable CAP system controls bacterial encapsulation and in vivo delivery profiles
Programmable CAP system controls bacterial encapsulation and in vivo delivery profiles Programmable CAP system controls bacterial encapsulation and in vivo delivery profilesIn this latest study, the research team focused on capsular polysaccharide (CAP), a sugar polymer that coats the bacterial surface, and developed a genetically encoded microbial encapsulation system, inducible CAP (iCAP), which Envelope polysaccharides can be regulated and dynamically expressed to enhance systemic delivery
.
sRNA knockout screen identifies key genes in CAP biosynthesis
sRNA knockout screen identifies key genes in CAP biosynthesis sRNA knockout screen identifies key genes in CAP biosynthesisBased on the small RNA screening of the capsular biosynthesis pathway, the research team constructed an inducible synthetic gene circuit that regulates bacterial encapsulation in Escherichia coli
.
By regulating the amount of isopropyl-β-D-thiogalactoside (IPTG), it is possible to control how long these synthetic bacteria survive in human blood
We "hijacked" the CAP system of the probiotic E.
coli strain Nisle 1917 , says first author of the study, Dr.
Dr.
Tetsuhiro Harimoto Dr.
Tetsuhiro Harimoto "hijacked" the CAP system of the probiotic E.
Schematic: Nisle 1917 strain engineered to escape killing by the avoidance system (macrophages) via capsular polysaccharides on the surface
Schematic: Nisle 1917 strain engineered to escape the killing system (macrophages) by capsular polysaccharides on the surface Schematic: Nisle 1917 strain engineered to escape the killing system (macrophages) by capsular polysaccharides on the surfaceThis dynamic dosing strategy increased the maximum tolerated dose of live bacterial therapy by 10-fold and improved antitumor efficacy in mouse cancer models
.
Furthermore, in situ embedding increased the proportion of bacterial translocations in mouse tumors, thereby improving the efficacy of distant tumors
.
Design and Characterization of iCAP Systems
Design and Characterization of iCAP Systems Design and Characterization of iCAP SystemsProfessor Kam Leong , one of the corresponding authors of the study, said bacterial cancer therapy has unique advantages over traditional drug therapy, such as effective tumor tissue targeting and programmable drug release, but potential toxicity limits its application
.
Today, the method proposed by our study may address this critical question!
iCAP system improves systemic delivery and efficacy of therapeutic bacteria
iCAP system improves systemic delivery and efficacy of therapeutic bacteria iCAP system improves systemic delivery and efficacy of therapeutic bacteriaCollectively, this study proposes a novel live bacterial therapy delivery system, inducible CAP (iCAP) , which can modulate the surface envelope polysaccharide according to the amount of IPTG to determine the fate of this synthetic bacteria - Evade immune attack or be eliminated
.
This programmable encapsulation system is expected to improve the therapeutic application of live engineered bacteria to cancer
.
Original source:
Original source:Harimoto, T.
, Hahn, J.
, Chen, YY.
et al.
A programmable encapsulation system improves delivery of therapeutic bacteria in mice.
Nat Biotechnol (2022).
https://doi.
org/10.
1038/s41587-022-01244 -y.