Synthetic Adhesome Cells: Engineering Interfaces Between Synthetic and Live Cells for Controlled Delivery

Multicellular organisms represent a remarkable transition in evolution, wherein single cells began working together to form a cohesive and coherent unit known as tissue. This transition was made possible by the emergence of cell-cell adhesion. Adhesions within tissue allow cells to communicate with their neighbors, both directly and indirectly, creating an integrated multi-cell circuit.

In one form of communication, cells can directly transfer material from one cell to another, which is a grand challenge for engineers that are trying to emulate cellular processes for delivery purposes. This research team will focus on user-defined transfer of material between synthetic cells and living cells, which will ultimately lead to new delivery mechanisms to alter biological behavior for biotechnology, chemical sensing, and biomedicine.

Finally, the project seeks to explore ethical issues with the proposed technology by collaborating with an ethicist and a variety of students from diverse backgrounds and to define design laws surrounding the use of synthetic cells.

Synthetic cells offer the promise of combining complex cellular machinery with precise molecular triggers and logic-gates to control cell-like processes for a variety of applications in biotechnology, chemical sensing and production, and biomedicine. A key capability of live cells, which has not been recapitulated by synthetic cells, is organization into functional multi-cellular tissue – the defining characteristic of all metazoans.

Cells within multi-cellular tissue communicate and contact one another through cell-cell junctions, such as adhesive junctions and junctions that enable diffusion of solutes from cell to cell, which are called gap junctions. The Belardi lab has developed synthetic cells that form functional adhesive junctions. This work makes use of adhesive and regulatory proteins – both natural and synthetic – to engineer multi-synthetic cell systems.

In parallel, the Stachowiak lab has shown that synthetic cells containing gap junction proteins can be used to transfer molecular cargo directly into the cytosol of live cells. Here, the project seeks to combine these two nascent capabilities to solve a key bottleneck in biotechnology – regulated delivery of biomolecules to the interior of cells. Specifically, the collaboration will build upon the natural ability of adhesive junctions to regulate the assembly of gap junctions, allowing precise, engineered control over molecular transfer between synthetic and live cells.

By providing regulatory control – a feature that native cells possess - this work will enable synthetic cells to reach their transformative and safe potential. The objective in this proposal is to take components and biophysical principles from adhesive cells and create “Synthetic Adhesome Cells”, with new functionalities that depend on optical triggers, co-adhesive partners and ligation-dependent logic-gates.

The overarching goal with the Synthetic Adhesome Cell platform is two-fold: i) to create systems with user-defined control over intracellular delivery and ii) to shed light on the biophysical mechanisms underlying junction formation and communication at cell-cell interfaces.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.