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Zhong et al. Chem Synth 2023;3:27 https://dx.doi.org/10.20517/cs.2023.15 Page 7 of 25

consuming mechanism need to be encoded in the network. Adding the fuel transforms the network from an
initial state to an active state by generating temporal output signals. Meanwhile, the fuel-consuming
mechanism in the network starts to deplete the fuel and drive the system back to its original state. At one
moment, the activating and deactivating processes of the network balance each other out. If the inflow of
the fuel molecule is persistently faster than its depletion, the network is kept in a function-active condition.
When fuel addition ceases, the network returns to the inactive state with the dissipation of the fuel
molecule. Therefore, regulated by the inflow performance of the fuel, precise spatiotemporal control of the
network structure and its output signals can be realized. Thanks to the programmability and predictability
of DNA reactions, the rational design of the nucleic acid-based dissipative network is demonstrated [95-109] . In
this section, we introduce the recent advances in nucleic acid-based dissipative networks for converting
environmental changes to diverse transient signals from the driving model of physically and chemically
fueled and enzyme-catalyzed systems.

Transient signals by physical and chemical fuels
The variations of physical and chemical triggers, such as the changes in light, pH, temperature, and
chemical states, can be transduced to molecular signals with temporal features to control biological
pathways in nature [83,85,110] . The versatile reconfiguration of nucleic acid structures allows us to easily set up
artificial reaction networks to sense external changes and transduce them to accessible molecular signals for
controlling downstream functions [35,88] . Inspired by nature, where the formation and breaking of disulfide
bonds can regulate the structures and functions of proteins to control biological pathways kinetically,
Grosso et al. designed a nucleic acid-based dissipative system by coupling allosteric DNA nanodevice and
the dynamic sulfur modulator . Figure 4A shows that the ligand-binding allosteric nanodevice is designed
[111]
to be a stem-loop DNA structure modified with two tails acting as allosteric sites. A disulfide bond is
conjugated to the middle of the DNA strand for a redox-responsive allosteric modulator complementary to
the two tails of the nanodevice. Upon the addition of the disulfide-linked DNA modulator to the allosteric
nanodevice, the interaction between the modulator strand and the allosteric sites of the nanodevice leads to
the release of the ligand. Once the disulfide bond in the modulator is reduced to the two thiolated halves,
the modulator splits into two short strands and spontaneously de-hybridizes from the nanodevice due to the
low bonding affinity. As a result, the DNA allosteric nanodevice restores its ligand binding ability, and the
system returns to its original state over time. The transient allosteric process of the nanodevice is highly
tolerant. The released ligand can be used as a time-dependent signal to regulate biological activities
temporally. The redox-induced disulfide-bond breakage was employed to control the assembly and
disassembly of the DNA-based nanotubes kinetically . The inhibitor strand locks the active strand of
[112]
DNA tiles to block assembling the tubular structure. And the disulfide-modified DNA strand is designed to
displace the inhibitor strand to trigger the assembly of the tubular structure. Concurrently, the disulfide-
modified DNA strand is reduced into two short DNA fragments in the presence of a reducing agent and
dissociates from the inhibitor strand, leading to the disassembly of the DNA nanotube. It is demonstrated
that the chemical signals can be transducted using the nucleic acid-based network for transient regulation of
DNA self-assembly.

In addition, dissipative pH value changes induced by chemical reactions are transduced by pH-responsive
[113]
C-G·C or T-A·T triplex structures . As depicted in Figure 4B, 2-(4-chlorophenyl)-2-cyanopropanoic acid
+
(CPA) and nitroacetic acid (NAA) are selected as chemical fuels for the dissipative operation of two pH-
responsive DNA nanodevices. As the typical pH modulators, CPA or NAA allows the time-dependent
control of the pH value of the solution. By adding chemical fuel to the solution, the pH value of the solution
can be rapidly decreased. Meanwhile, the chemical fuel gradually dissipates through decarboxylation,
leading to an increased pH value back to the initial state. In the first case, a DNA-based nanoswitch is