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21ENGBIO Controllable DNA polycatenanes of infinite length for intelligent biomaterials

Reference	BB/W01338X/1
Principal Investigator / Supervisor	Professor Susan Rosser
Co-Investigators / Co-Supervisors	Dr Christine Merrick
Institution	University of Edinburgh
Department	Sch of Biological Sciences
Funding type	Research
Value (£)	100,810
Status	Completed
Type	Research Grant
Start date	31/01/2022
End date	30/01/2023
Duration	12 months

Abstract

DNA hydrogels have state-of-the-art applications in regenerative therapy and biologics delivery. The main disadvantages of current DNA hydrogels are in how they are held together. Covalently cross-linking DNA with small molecules increases assembly time and reagent costs and risks potential toxicity of residual unreacted small-molecule cross-linkers; and structures that rely on DNA strand annealing (hydrogen bonds) are design-heavy and easily unravelled by changes in environmental conditions such as an increase in temperature. Here, we will synthesise never-before-made DNA-based materials from chain-like polymers called polycatenanes. These materials will require no cross-linking small molecules and will not unravel upon changes in environmental conditions. Despite Nobel Prize-worthy work from Professor Jean-Pierre Sauvage in which two ring-shaped molecules were linked together forming a two-noded catenane, a polycatenane of infinite length remains an elusive goal in polymer chemistry. We have devised a strategy to enzymatically polymerize DNA plasmids to make polycatenanes of infinite and controlled lengths in rapid benchtop reactions. In addition to synthesising 1D DNA chains, our strategy will enable connectivity of DNA polycatenanes to make 2D (branched) and 3D (mesh-like) structures. These structures will be assembled in vitro, analysed by agarose gel electrophoresis, and imaged with atomic force microscopy and transmission electron microscopy. This work will set a precedent for a new nanoarchitechtonic platform for intelligent biomaterials with tuneable rheology. These biomaterials will have applications in biologics delivery and regenerative medicine such as smart hydrogels for simultaneous in situ diagnosis of diseases and responsive administration of treatments.

Summary

DNA is an ideal substrate from which to construct new materials for medical applications because it is sustainable, biodegradable, biocompatible, non-toxic, and highly programmable. DNA hydrogels have state-of-the-art applications in regenerative therapy (like stimulating new tissue growth from stem cells) and biologics delivery (like controlled, sustained release of insulin). They are squishy, gel-like materials made of water and web-like structures of DNA, and they can obtain unique properties when combined with nanomaterials. The disadvantages of current DNA hydrogels are in how their web-like structures of DNA are held together. Many rely on the ability of compatible DNA strands to stick together but this stickiness is susceptible changes in environmental conditions such as an increase in temperature which causes the structures to unravel. Adding small molecules to reinforce the DNA structures through cross-linking increases the manufacturing time and cost. Here, we will synthesise never-before-made DNA-based materials from polycatenanes. Polycatenanes are polymers in which molecular rings are mechanically linked together akin to the links of a chain. We have devised a strategy to make DNA polycatenanes of infinite and controllable lengths using enzymes to connect rings of DNA. In addition to enabling assembly 1D DNA chains, our strategy will enable construction of 2D and 3D DNA structures that require no cross-linking small molecules and will not unravel upon changes in environmental conditions. This work aims to seed development of a new family of structurally unique DNA-based biomaterials for programmable biologics delivery and patient-specific regenerative therapies.

Committee	Not funded via Committee
Research Topics	Synthetic Biology, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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