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5.5 Examples of combinatorial logic gates using half‐adder and full‐adder. (a) Half‐adder circuit diagram containing XOR and AND logic gates and its truth table. (b) Example of addition operation by the half‐adder that adds the two least significant bits highlighted in puncture/dashed line. (c) Circuit schematic and truth table for full‐adder. (d) Secondary structures demonstrating design principles for the Broccoli aptamer (XOR gate) and MG RNA aptamer (AND gate) and their fluorescence outputs in response to DNA inputs.

      Source: (Panel c) Adapted from Goldsworthy et al. [46]; (Panel d) From Goldsworthy et al. [46]. Licensed under CC by 4.0.

An RNA tetragonal structure with infusion of two different light‐up RNA aptamers acting as AND (MG‐binding aptamer) and XOR (Broccoli aptamer) gates was fused into a tetragonal particle to fabricate the half‐adder circuit. These gates utilize the same DNA inputs but produce two distinctly different fluorescence emissions as output signals, SUM (λ_em = 510 nm) and CARRY (λ_em = 650 nm). Both the MG RNA aptamer and Broccoli RNA aptamers were incorporated on alternating vertices of the tetragon. To satisfy the XOR and AND truth values (in absence of inputs 0‐0 the output must be OFF), additional DNA inhibitor (XOR_DNA and AND_DNA inhibitors) strands were introduced to interfere the corresponding ON states of both aptamers (Figure 5.5c). The fluorescence readout corresponding to XOR and AND operations was achieved by relying on the displacement principle between inhibitor DNA strands, DNA inputs, and RNA aptamers. Specific design approaches including RNA and DNA sequences chosen for combinatorial implementation of the AND and the XOR gates to satisfy the requirements for a half‐adder have been published [46]. The next step is construction of a full‐adder based on RNA light‐up aptamer, which has yet to be achieved. The full‐adder circuits extend the concept of the half‐adder by providing an additional carry‐in (Cin) input as demonstrated in the diagram in Figure 5.5c. This design has three inputs (A, B, and Cin) and two outputs (Sum and Carry‐out).

5.4 Conclusion

      The integration of advances in nucleic acid nanotechnology and in nucleic acid aptamer technologies makes it possible to build novel nanoparticles playing intermediate roles between electronic computers and biological systems. Programming with biological molecules, especially with nucleic acids (NA), is now becoming very attractive due to their potential of functions ranging from simple fluorescence emission to sophisticated gene regulation in vivo. The structural behavior encompassed within their sequences can be predicted and manipulated using 2D folding algorithms. The resulting nucleic acid biopolymers can then be used as logic‐gated nano‐agents for specific biomedical applications. Fluorogenic RNA aptamers can be designed to function as a simple circuit within individual binary logic gates. This demonstrates the great potential of nucleic acid nanotechnology and holds promise to develop cutting‐edge technologies, especially if synergistically combined with other computing and nanorobotic systems.

Acknowledgments

      This work was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R03EB027910. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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