ERV Syncytin-Functionalized EVs for Selective Cargo Delivery
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Solution Overview
Problem
Existing delivery systems for therapeutic agents face challenges in selectively targeting specific cells within the body, as they often induce immunogenic responses and have suboptimal pharmacokinetics and biodistribution.
Innovation Solution
Extracellular vesicles (EVs) are functionalized with ERV syncytin, which allows them to selectively target and deliver therapeutic agents to specific cells by exploiting the fusogenic properties of syncytin proteins, enhancing membrane transport and reducing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing delivery systems are used to deliver therapeutic agents, then therapeutic delivery can be achieved, but selective targeting of specific cells is poor and immunogenic responses are induced
Solution Approach 1:
The patent uses ERV syncytin proteins as intermediary molecules that mediate the interaction between EVs and target cells. These syncytin proteins are incorporated into the EV membrane, enabling the EVs to bind to specific receptors (such as ASCT2) on target cells through the syncytin-receptor interaction, thereby achieving selective targeting while the EV capsule protects the immunogenic therapeutic cargo
Solution Approach 2:
The patent exploits the natural biological system of extracellular vesicles as a copy of physiological delivery mechanisms. By using naturally occurring EVs rather than artificial delivery vehicles, the system mimics biological processes that cells already recognize and tolerate, reducing immunogenicity while maintaining delivery functionality
2Reliability
If artificial delivery vehicles are used, then cargo delivery capability is achieved, but immunogenicity increases compared to physiological carriers
Solution Approach 1:
The patent employs extracellular vesicles, which are naturally produced by cells, to perform the delivery function. These physiological carriers already exist in the body and perform natural functions, so using them for therapeutic delivery leverages their inherent biocompatibility and reduced immunogenicity while maintaining effective cargo delivery capabilities
Solution Approach 2:
The patent modifies the surface properties of EVs by incorporating ERV syncytin proteins, which changes the binding characteristics without fundamentally altering the physiological nature of the carrier. This parameter change enables specific targeting while preserving the low immunogenicity of natural EVs
3Reliability
If EVs are loaded with therapeutic agents, then targeted delivery potential is achieved, but membrane transport efficiency needs enhancement
Solution Approach 1:
The ERV syncytin proteins serve as intermediary molecules that facilitate membrane transport. These proteins have known fusogenic properties that enable them to mediate membrane fusion or translocation events, thereby enhancing the efficiency of cargo delivery across the target cell membrane while maintaining targeted delivery through receptor-specific binding
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 ERV syncytin-functionalized EVs provide a bio-mimetic delivery system that efficiently targets and delivers therapeutic agents to specific cells, improving pharmacokinetics and biodistribution while minimizing immune response.
Implementation Method 1
exploiting the fusogenic properties of syncytin proteins, enhancing membrane transport
Data Source
AI summary
EVs are being recognized as vectors for drug delivery. In particular. EV loading with targeting and therapeutic agents brings along an interesting opportunity to translate EVs into a bio-mimetic selective delivery system. Indeed. EVs constitute a physiological carrier being potentially less immunogenic than artificial delivery vehicles. The inventors now developed a novel method to control the loading of a cargo into EVs on demand. These EVs are equipped, if necessary, with non-viral fusogen, therefore enhancing EV-cargo delivery into acceptor cells. To acutely measure this process, they follow the fate of a luciferase-tagged cargo. Cargo loading was enabled through a drug-reversible inducible dimerization system. Briefly, donor cells were transfected with plasmids encoding for FKBP-tagged CD63, a classical membrane EV marker, and FRB-Nanoluciferase (NLuc) that is normally cytosolic. Upon addition of the dimerizing drug. FRB-Nluc interacts with FKBP-CD63 and is recruited into secreted EVs. This is accompanied by an enhanced delivery into acceptor cells. This phenomenon can be further enhanced when EVs are equipped with syncitin1, a mammalian fusogenic protein that trigger fusion between EV membrane and the plasma membrane of acceptor cells. Using this novel process, the inventors further demonstrated that the catalytic domain of the Diphteria toxin (DTA), that is responsible for protein synthesis inhibition and ultimately cell death, can be delivered to acceptor cells via functionalized EVs. This led to protein synthesis inhibition and death of acceptor cells. This novel method and the derived applications promise to open new doors in precision care medicine, especially when EVs will be equipped with antibodies raised against cell specific antigens.