Engineered Microbial Cells with Modified T3SS for Extracellular Delivery
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Solution Overview
Problem
Current engineered microbial cells using Type 3 Secretion Systems (T3SS) deliver therapeutic molecules directly into host cells, limiting access to extracellular targets, and existing methods for delivering therapeutic molecules to the extracellular space are inefficient.
Innovation Solution
Engineered non-pathogenic microbial cells with a modified T3SS-derived extracellular secretion system (TDESS) that secretes therapeutic molecules into the extracellular space, allowing interaction with cell surface receptors and signaling molecules, and can be used to deliver anti-inflammatory peptides and antibodies to specific targets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a Type 3 Secretion System (T3SS) is used to deliver therapeutic molecules, then delivery into host cells is achieved, but access to extracellular targets is limited
Solution Approach 1:
The T3SS is segmented into two functional components: the secretion apparatus (for exporting therapeutic molecules) and the translocation apparatus (for injecting into cells). By separating these functions, the system can selectively deliver to either intracellular or extracellular targets depending on which components are present, thus resolving the contradiction between reliable delivery and target accessibility versatility.
Solution Approach 2:
Instead of using the complete T3SS for intracellular delivery, the invention inverts the approach by using only the secretion apparatus components (VirB, MxiG-MxiK, Spa proteins) without the translocation components (IpaB, IpaD, MxiC). This inversion allows therapeutic molecules to be secreted into the extracellular space rather than injected into cells, expanding target accessibility while maintaining delivery efficacy.
2Adaptability or versatility
If existing methods are used to deliver therapeutic molecules to the extracellular space, then extracellular targets can be accessed, but delivery efficiency is low
Solution Approach 1:
The engineered microbial cell acts as an intermediary vehicle that carries the T3SS-derived secretion apparatus to the target site. This intermediary system efficiently transports therapeutic molecules directly to the extracellular space near target cells, overcoming the inefficiency of conventional delivery methods while maintaining accessibility to extracellular targets.
Solution Approach 2:
The invention changes the delivery parameters by using a biologically active secretion system rather than passive diffusion or conventional transfection methods. The T3SS-derived apparatus actively secretes therapeutic molecules with high efficiency, transforming the delivery mechanism from inefficient to highly productive while maintaining extracellular target accessibility.
3Reliability
If pathogenic bacteria are used for therapy, then T3SS delivery capability is available, but safety concerns arise
Solution Approach 1:
The harmful pathogenic components (toxins, invasion plasmid antigens IpaB/IpaD, and gatekeeper MxiC) are extracted from the original T3SS system. Only the beneficial secretion apparatus components (VirB, MxiG-MxiK, Spa proteins) are retained and reengineered for therapeutic use, eliminating pathogenicity while preserving delivery capability.
Solution Approach 2:
The invention converts the potentially harmful T3SS system into a beneficial therapeutic tool by removing pathogenic elements and redirecting the secretion apparatus to deliver therapeutic molecules rather than toxins. The same molecular machinery that caused harm is now used for benefit, treating diseases while eliminating the harmful effects.
Data Source
AI summary
Described herein are compositions and methods relating to engineered bacteria which have a modified Type 3 Secretion System (T3SS) which permits them to deliver proteins to the extracellular space (e.g., as opposed to the intracellular space of a target cell as done with a wild-type T3SS). In some embodiments, the engineered bacteria comprise a transgenic T3SS. In some embodiments, the delivered protein is non-native or transgenic with respect to the engineered bacteria.