Virulence-Attenuated Bacterial Protein Delivery via Type III Secretion
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Solution Overview
Problem
Current methods for delivering therapeutic proteins or peptides into eukaryotic cells, particularly for cancer treatment, face challenges such as low efficacy, degradation in lysosomes, and the conflict between stability in the human body and targeted release within cells, with existing bacterial strains lacking simplicity in cloning and broad application.
Innovation Solution
Development of recombinant virulence attenuated Gram-negative bacterial strains with enhanced heterologous protein expression and secretion capabilities, utilizing type III and IV effectors to deliver proteins like viral and functional eukaryotic proteins into cancer cells, stabilized over days to weeks in vivo, through engineered nucleotide sequences and deletions of essential genes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current methods for delivering therapeutic proteins into eukaryotic cells are used, then delivery can be attempted, but efficacy is low and cargo is degraded in lysosomes
Solution Approach 1:
The patent uses bacterial type III secretion system effectors as intermediary molecules to mediate the delivery of therapeutic cargo into eukaryotic cells. These effectors act as carriers that facilitate translocation across the cell membrane, protecting the cargo from lysosomal degradation and enabling effective intracellular delivery.
Solution Approach 2:
The patent replaces conventional mechanical delivery methods (such as microporation or nanoparticle transfection) with a biological secretion system. The bacterial type III secretion system provides a natural, efficient mechanism for protein translocation that overcomes the limitations of physical delivery methods, achieving higher efficacy without cargo degradation.
2Stability of the object's composition
If stability of cargo-carrier in the human body is increased, then protection is improved, but release within the target cell becomes more difficult
Solution Approach 1:
The patent applies local quality by designing the cargo-carrier system with different stability characteristics at different locations. The bacterial effector-cargo conjugate remains stable during circulation in the human body, but undergoes controlled destabilization and cargo release specifically within the target cell through the secretion mechanism, achieving both protection and targeted delivery.
Solution Approach 2:
The patent introduces dynamic properties to the cargo-carrier system. The bacterial effector maintains a stable complex with the therapeutic cargo during transport, but the system dynamically transitions to cargo release upon entering the target cell. This dynamic behavior allows the same system to provide both stability during circulation and controlled release at the destination.
3Adaptability or versatility
If existing bacterial vectors are used for protein delivery, then delivery capability is provided, but cloning simplicity and broad application are hindered
Solution Approach 1:
The patent creates a universal bacterial vector system based on the type III secretion system that can deliver multiple different therapeutic cargos. The system uses a common effector platform that can be adapted to carry various proteins, peptides, or other therapeutic molecules, enabling broad application across different disease targets while maintaining relatively simple cloning procedures through standardized vector designs.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The strains effectively deliver therapeutic proteins to cancer cells, inducing apoptosis and interferon responses, demonstrating significant tumor growth delay and regression in animal models.
Implementation Method 1
The type III secretion system (T3SS) used by bacteria like Yersinia, Shigella and Salmonella functions like a nano-syringe that injects so-called bacterial effector proteins into host cells.
Implementation Method 2
the recombinant virulence attenuated Gram-negative bacterial strains allow the translocation of various type III effectors, but also of type IV effectors, of viral proteins and most importantly of functional eukaryotic proteins into cancer cells
Data Source
AI summary
The present invention relates to recombinant virulence attenuated Gram-negative bacterial strains and its use in a method of treating cancer in a subject.