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Page 4 of 25 Zhong et al. Chem Synth 2023;3:27 https://dx.doi.org/10.20517/cs.2023.15

Figure 1. (A) Schematic assembly of a [2 × 2] nucleic acid-based constitutional dynamic network (CDN); (B) The modular construction
of the constituents of [2 × 2] CDNs by integrating metal-ion-dependent DNAzyme units as reporter domains and triggering domains as
functional units; (C) The orthogonal operation of a [2 × 2] CDN using different triggers and the subsequent recovery of CDN by
respective counter-triggers. Figure 1C is quoted with permission from Wang et al. [63] .

number of constituents enhanced the complexity of the system towards organizing nine constituents in a
[62]
[3 × 3] network . Three-dimensional (3D) engineering CDNs can achieve further complexity . For
[66]
example, a 3D CDN system with eight constituents, AB C, was accessed using the three-junction
i i
i
constituents composed of components A , A , B , B , C , and C . 2D [3 × 3] and 3D [2 × 2 × 2] CDNs include
2
1
2
2
1
1
a series of intercommunicating sub-[2 × 2] CDNs that can be reconfigured by different auxiliary triggers .
[66]
By applying successive stimuli to these networks, the hierarchically adaptive reconfiguration of the
compositions of these CDNs was demonstrated .
[62]
Feedback and feedforward
The feedback loop and feedforward loop are the overrepresented network structures in nature [67,68] . Many
complex dynamic networks comprise feedback and feedforward loops [17,69-71] . For instance, autonomous
oscillations require a delayed negative feedback process that pushes the system back by repressing the
autocatalytic species . Nucleic acid-based artificial dynamic networks with feedback and feedforward
[72]
mechanisms have been well-studied [73-75] . For example, the adaptive features of nucleic acid-based CDNs
were applied to assemble feedback-driven CDNs . Figure 2A outlines the schematic diagram of feedback-
[75]
driven adaptive reconfiguration of nucleic acid-based CDN . The CDN is composed of four constituents,
[75]
CC′, DD′, CD′, and DC′, each of which is equipped with four different Mg -ion-dependent DNAzymes as
2+
reporter units. In the presence of hairpin H , DD′ modified with an additional Mg -ion-dependent
2+
1
DNAzyme as a signal activator unit cleaves H and yields fragment E for signal transmission. E stabilizes
1
1
1
+
the signal receptor constituent CC′ through the complementary sequences and the formation of a K -ion-
stabilized G quadruplex (CC′-K ), leading to the upregulation of constituents CC'-K and DD′ and
+
+
concomitantly downregulation of constituents CD′ and DC′. The upregulation of DD' further accelerates the
catalytic cleavage of H for a positive feedback pathway driving the adaptive reconfiguration of CDN R.
1
Alternatively, a negative feedback-driven adaptive reconfiguration of CDN R was also designed using
hairpin H as an external trigger. Using experimental and computational means, the feedback-driven
2
adaptive behaviors were illustrated by the time-dependent concentration changes of each constituent of
CDNs. The feedback mechanisms provide promising means to construct the signal amplification platform