Future

Additional Experiments for GIFTs Implementation

Connection and Molecular Transport between GUVs via DNA Nanopores

1.Smart in vivo drug delivery systems (Smart DDS)

The GIFTs consists of a multicompartmental structure composed of an outer liposome and inner liposomes. Each liposome is functionalized with DNA origami nanopores, they are further modified with DNA strand displacement reactions. Specific external DNA signals can pass through the DNA nanopores on the outer liposome and reach the inner liposomes. With DNA strand displacement reaction,the nanopores undergo conformational opening and dock,thereby enabling precise control over the release of drugs or biomolecules.

Additional Experiments for GIFTs Implementation

To implement the GIFTs system, further experiments will be required beyond those conducted during the summer project. A brief overview is provided below.

Connection and Molecular Transport between GUVs via DNA Nanopores

The Docking–Undocking System, designed to achieve the selective drug release function of GIFTs and driven by a strand displacement reaction, has already been confirmed to operate as intended.

For future implementation, it will be necessary to drive this system on GUV-in-GUV structures to verify that DNA nanopores can connect the inner and outer liposomes, enabling molecular transport between them.

This additional experiment is expected to bring GIFTs implementation closer to realization.

Future Applications

This technology is expected to have applications in the following fields:

1.Smart in vivo drug delivery systems (Smart DDS)

The proposed vesicular system enables the selective release of drugs from specific inner liposomes at predetermined time points, triggered by external DNA signals transmitted through the DNA nanopores of the outer liposome. This approach not only allows site-specific functionality but also provides control over the diversity of encapsulated cargo and the timing of their release. Such precise control is highly promising for the simultaneous administration of multiple therapeutics and the reduction of side effects. In combination with specific ligands (e.g., aptamers, DNA strand displacement reactions) or stealth modifications (e.g., PEGylation, glycan modification) [1], this system could be applied to a wide range of disease treatments, including cancer therapy and site-specific inflammation control.

2.Artificial cells

The vesicular system allows the incorporation of multiple compartments with distinct functions within the same structure, making it suitable for constructing multistep reactions or metabolic pathways in artificial cells. By activating only specific inner liposomes through external DNA signals, the order and timing of reactions can be finely tuned. This technology contributes to the emulation cellular functions and the construction novel biosynthetic systems. Controlling the sequence of reactions enables temporal regulation regulation of reaction pathways, which has been difficult to achieve with conventional vesicular systems. Consequently, this approach may lead to the development of programmable, multicompartmentalized artificial cells and environmentally responsive bioreactors.

3.Selective energy utilization

The vesicular system can regulate the responsiveness of inner liposomes through external DNA signals, enabling selective utilization of energy. Previous studies on selective energy utilization have incorporated ATP synthesis machinery or light-driven proton pumps into inner liposomes, where external signals trigger energy production for targeted intracellular sensors [2]. In our proposed system, giant unilamellar vesicles (GUVs) with large internal volumes and expanded membrane surface areas are employed as inner compartments, providing enhanced capacity for housing energy-conversion components such as ATP synthase and light-driven proteins.

Reference

[1] M. L. Immordino, F. Dosio, and L. Cattel, “Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential,” International Journal of Nanomedicine, vol. 1, no. 3, pp. 297–315, 2006. [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2426795

[2] S. Berhanu, T. Ueda, and Y. Kuruma, “Artificial photosynthetic cell producing energy for protein synthesis,” Nature Communications, vol. 10, Art. no. 1325, 2019. [Online]. Available: https://doi.org/10.1038/s41467-019-09147-4

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