DNA nanodevices and the immune system: friend or foe?

Synthetic DNA-based nanodevices offer tremendous promise as drug delivery capsules and diagnostic tools in living systems. In a recent perspective (Surana et al. Nat. Nanotechnol. 2015), we outline possible outcomes of the interactions between DNA nanostructures and the immune system, and envision potential design principles in these architectures to circumvent the multifaceted defense machinery of higher organisms.

HFSP Program Grant holder Yamuna Krishnan and colleagues
authored on Tue, 27 October 2015

The physico-chemical properties of DNA that make it an ideal coding molecule for genetic information have also led to its exploitation as a scaffold to build higher order structures at the nanoscale. Such synthetic DNA-based nanostructures – complex architectures designed to assemble from short sticky pieces of DNA – have been deployed in cells as cargo-carrying capsules and diagnostic agents. Such carriers and probes have promising applications in the fields of diagnostics and therapeutics in higher organisms. However, the immune system of these organisms often detects foreign DNA as a viral infection, much like the flu, and thus, attempts to efficiently eliminate it from the system. In a recent study described in Nature Nanotechnology, we used insights from the detection and elimination machinery present in vertebrates to lay out a framework to better design DNA nanostructures so as to sculpt and/or evade the immune system for wider applicability.

Cells protect against foreign DNA by first sensing and binding to the DNA, which induces increased expression of a large number of genes. These genes produce signaling proteins (called interferons), which in turn lead to expression of other genes. The combined action of these gene products leads to an antiviral and inflammatory response to the exogenous DNA, which also facilitates long-term responses to infection. Prolonged activation of these processes by foreign DNA, however, can be toxic to the organism. After eliciting these cellular and molecular responses, DNA is cleaved by enzymes and disposed of. Many of these mechanisms are often redundant, hence increasing the efficiency of detection and disposal.

Thus, for DNA nanostructures to find applications in higher organisms, it is imperative to incorporate strategies in synthetic DNA nanodevices to either tune or evade these surveillance mechanisms so as to increase their lifespan in these organisms – many of these strategies have been based on observations made in silico and in isolated cells. One way to tune immune responses to a given DNA architecture is to hide sequences of DNA that tickle the detection machinery while exposing those that are relatively benign. Nanostructures devoid of free ends are more stable to enzymatic degradation than counterparts which have accessible termini, and could be designed to evade the immune system by encapsulating them in a polymer coating that resembles the cellular plasma membrane. The DNA scaffold could also be designed to incorporate non-natural chemically modified base pairs, backbones and sugar moieties. We envision that further development and incorporation of such design principles could lead to the fabrication of an ‘ideal’ DNA nanostructure that could potentially work with the immune system of complex organisms to find exciting applications in immunotherapy, re-programming of transcription programs and tissue regeneration.

Reference

Designing DNA nanodevices for compatibility with the immune system of higher organisms.Surana, S., Shenoy, A.R. and Krishnan, Y. Nat. Nanotechnol. 10, 741-747 (2015).

Pubmed link