Healing Tissues via Programmable DNA Nanotechnology

Growth factors are powerful biological proteins that cells produce and release. They have a key role in instructing our cells how to grow from one cell as an egg into approximately 30 trillion cells that are arranged in a coordinated fashion to create a person. Their influence also continues throughout our lives; if tissues are damaged such as a broken bone or wound on our skin, growth factors coordinate how our tissue heal. Because of this powerful influence, growth factors are highly attractive substances to use as therapeutics to promote tissue repair. While several are used in clinics around the world, their efficacy, safety, and impact are all far from being optimal due to sub-optimal efficacy and a high cost of production. Therefore, in order to truly realise their potential as therapeutics, we need new strategies that revolutionise how we use growth factors clinically.

In this proposal, we will combine aspects of materials science, nanotechnology, and biology to develop a transformational approach to using growth factors as therapeutics. Our approach relies on designing novel nanotechnology-enabled materials that actively harvest growth factors from within the body to then use as therapeutics to heal tissues. This strategy will eliminate the need to produce expensive proteins, dramatically reducing the cost of treatment. Furthermore, it will enable the adaptation of previously approved therapeutics to new areas in tissue repair, speeding up the development of new treatments while also minimising production expenses.

We will demonstrate the ability of our new approach to heal critical size bone defects - that is, bone defects that are too large to naturally heal on their own. This data forms a key component of justifying the translation to the clinic, making this proposal instrumental in bringing this exhilarating new technology to the bedside.

This proposal will develop a transformational bioinspired nanotechnology platform that shatters current gold-standard technologies to enable a paradigm shift in how we use growth factors as therapeutics. Inspired by the 'large latent complex' that our bodies use to rapidly activate localised TGF-beta (DOI: 10.1016/j.matbio.2015.05.006) - the only example of a mechanically activated growth factor - our TrAP platform is a fully synthetic technology that harnesses cellular traction forces to activate latent growth factor activity. Based on the flexibility of aptamer technology, the TrAP platform is theoretically adaptable to mechanically activating and delivering ANY therapeutic protein of interest. As such, it has the potential to revolutionise the way we treat damaged tissues throughout the body, whether it is bones, tendons, skin, nerves, muscle, or more.

Due to the inherent nature of aptamers to bind ligands with picomolar affinities, we hypothesise that the TrAP platform will be able to harvest, concentrate, and protect endogenous growth factors at sites of tissue damage, subsequently activating them at therapeutic concentrations upon application of cellular traction forces. This will form a truly disruptive technological breakthrough, fundamentally rewriting existing cost structures for using growth factors as therapeutics; by eliminating the need to use recombinant proteins, it will usher in a wave of low-cost, bioactive materials that actively promote tissue repair. Furthermore, activation of growth factors via TrAP unfolding inherently relies on integrins binding the TrAPs and applying tension. This has the potential to promote synergistic receptor tyrosine kinase and integrin signalling that has been robustly demonstrated to boost biological impact (DOI: 10.1530/JOE-10-0377).

Importantly, there currently exists a healthy industrial community focused on developing aptamer-based therapeutics for inhibiting protein activity. This provides a significant opportunity for repurposing these inhibitory aptamers for unaddressable tissue repair markets, reducing development costs, regulatory burden, and increasing the speed to translation. Details on these market opportunities and the ability to develop products that give rise to inward investment and wealth creation, while simultaneously driving down NHS costs are detailed in the Pathways to Impact (PtI).

However, these current market opportunities are only the beginning of the full potential that is provided by the TrAP platform. As designed, TrAPs are highly amenable to every substrate of interest ranging from sponges, to minimally invasive injectables, to next-generation 3D printed scaffolds. It is this latter area that has the potential to extend the transformational impact of TrAPs far into the future; by spatially patterning different TrAPs within 3D printed scaffolds, it may be possible to guide the growth of hierarchical tissue structures, coordinating the growth of blood vessels, nerves, lymphatics, and other tissue-specific structures via direct growth factor-mediated guidance and activation of engineered spatiotemporal paracrine signalling gradients. As structured, the TrAP platform is the ONLY technology that inherently possesses this ability, making it an exemplar paradigm-shifting technology that combines the fields of 'Advanced Materials' with 'Regenerative Medicine', two of the UK's Eight Great Technologies, to create impact from the bench to the bedside.

Hand-in-hand with developing this transformational technology is the training of highly qualified interdisciplinary scientists. This proposal will enable the training of a PDRA, along with several students in highly interdisciplinary skills that address EPSRC CDT priorities, as detailed in the PtI. These individuals will extend the impact of this proposal by harnessing this training to contribute to continual advancement of the UK economy through disruptive research and development for years to come.