Rigidity dependent formation process of DNA supramolecular hydrogel

doi:10.21203/rs.3.rs-1996474/v1

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Rigidity dependent formation process of DNA supramolecular hydrogel

https://doi.org/10.21203/rs.3.rs-1996474/v1

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published 25 Nov, 2022

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A DNA building block with tunable rigidity was constructed and the hydrogel formation process has been investigated accordingly. The high rigidity has been demonstrated to facilitate the fast gelation. Different pathways were revealed between the rigid and flexible building block and a cyclized dimer intermediate has been proposed. The energy barrier of the ring open process has also been proved to play a fundamental role in determining the gelation kinetics. Furthermore, the hydrogel molecular network rigidity was also tuned in situ through strand displacement, which also support the kinetic control mechanism in the formation process of DNA hydrogel.

Hydrogels are a class of three-dimensional network materials with high water content^1–3, which have been widely utilized in biomedical applications^4–7. During the past few decades, DNA has arisen as a promising material for construction of supramolecular hydrogels through the complementary base pairing^8–12. The rigid DNA duplex network excludes the small size meshes and endows the hydrogel with high permeability^13,14. Meanwhile, the dynamic property of the DNA hybridization also provides the hydrogel excellent injectability, self-healing and shear-thinning properties^15–18. Furthermore, the designability of DNA sequence has also brought the good stimulus responsiveness to DNA supramolecular hydrogels^19–24. Therefore, DNA supramolecular hydrogels have been used in three-dimensional cell culture^25,26, spinal cord repair²⁷, osteoarthritis treatment²⁸, heavy metal ion detection^29,30 and drugs delivery^31–33.

Compared with traditional hydrogels, the distance of cross-linking points in DNA supramolecular hydrogels is usually shorter than the persistence length of DNA double strand, which brings DNA supramolecular hydrogels with rigid network^13,14,27. It has been well demonstrated that the rigidity of the molecular network plays important roles in the mechanical properties of the hydrogel^34–37. For example, Liu et al. introduced conformation transition of the building block between flexible single strand and i-motif quadruplex to tune the rigidity of the molecular network, which increased the mechanical strength from 250 Pa to 1000 Pa³⁴. The same group also reported the collapse of PPO (polypropylene oxide) segments in the hydrogel network could increase its rigidity, thus improving the mechanical strength³⁵. These examples have successfully demonstrated the molecular network rigidity determines the mechanical strength of the DNA supramolecular hydrogels.

In the previous studies, the fast formation of the DNA supramolecular hydrogels in seconds have been observed, which was explained by the rigidity of the building blocks¹⁹. The rigidity would potentially determine the gelation process through tuning the dynamic balance between cyclization and chain extension of the building blocks, which has been proved in the linear supramolecular polymerization systems^38–40. For example, Zhang et al. designed a bifunctional monomer with self-sorting property and demonstrated the increased monomer rigidity could further promote the supramolecular polymerization³⁸. Liu et al. also reported the formation of rigid duplex in the central part of flexible single-stranded DNA would facilitate the “ring-open” polymerization³⁹. While the importance of the monomer rigidity on the supramolecular polymerization has been well recognized, how the rigidity of the building block affects the supramolecular gelation process has been rarely studied.

Herein, we constructed a rigidity-tunable building block to investigate the kinetic process of the hydrogel formation through backbone remodeling. Different pathways have been revealed between the rigid and flexible building block, and the conversion between intramolecular and intermolecular interactions was confirmed. Furthermore, the hydrogel molecular network rigidity was also tuned in situ, supporting the kinetic control mechanism. Our results revealed the rigidity effect of building block on hydrogel formation kinetics, which may benefit the application of DNA supramolecular hydrogels in smart devices and bio-mimic materials.

As illustrated in Fig. 1, the branched DNA molecule (B-i) was composed of three identical arms, which were chemically branched to a central unit. A half i-motif sequence was integrated at the end of each arm as cross-linker (11 nt, blue), which could be partially protonated and formed full quadruplex i-motif structure with another arm under acid conditions. To tune the rigidity of the building block, backbone segment (15 nt, orange) was also designed in the core region. With the addition of the complementary sequence cBi, the 15 bp duplex would form in the core region, which was shorter than the persistence length of B-helix DNA and therefore, the flexible building block turned to rigid form (RB). Then the different gelation kinetic processes between the flexible and rigid building block could be investigated by changing the order of pH adjustment and DNA hybridization.

As previously reported¹⁵, commercially available branched phosphonamidite was employed for the synthesis of branched B-i molecule (Sequence can be found in Table S1), which was characterized by 20% denaturing polyacrylamide gel electrophoresis (PAGE). As shown in Fig. 2a, the sharp and clear band (Lane 4) indicated the high purity of the synthesized product. Compared with the linear sequences I, 2I, and 3I (With the same repeated sequence as B-i, illustrated in Table S1), B-i showed a slower migration rate, which was due to the larger hydrodynamic volume of branched structure. The molecular weight was detected as 23926 g/mol by MALDI-TOF MS (Fig. S1), which matched the theoretical molecular weight of 23913 g/mol. These results demonstrated that the branched DNA molecule B-i was successfully synthesized and purified.

Then, the assembly behavior of B-i was studied. As shown in Fig. 2b, under 10% native PAGE, when the cBi (Sequence can be found in Table S1) was added to B-i in a molecular ratio of 3:1 at pH 8.00, the clear band demonstrated the efficient hybridization between B-i and cBi (Lane 5). Further, when the molecular ratio decreased to 2:1, four bands appeared (Fig. S2, Lane 3), which respectively corresponded to B-i, B-i + cBi, B-i + 2cBi and B-i + 3cBi. These results can be explained that the assembly of each arm of B-i and cBi was random and independent of each other. The assemble behavior of B-i and cBi under basic condition suggested we could construct the rigid building block (RB) through DNA hybridization.

Next, we investigated the formation of i-motif by Circular Dichroism (CD) spectrum. As shown in Fig. 2c and Fig. S3, there was a positive peak in 282 nm, a negative peak in 246 nm and a crossover at 257 nm under acid conditions for both B-i and RB, which reflected the formation of i-motif. It was worth noting that the CD intensity of i-motif was very similar at different pH for B-i (Fig. 2c) while the i-motif signal intensity decreased with the increase of pH for RB (Fig. S3). As a control, the CD spectrum of the linear sequence I was also investigated, which could only form intermolecular i-motif. The pH dependent density of the I was observed (Fig. S4) similar to RB, suggesting the potential intermolecular i-motif in RB and the intramolecular i-motif in B-i. These results indicated that the rigidity difference of the branched units would bring different cross-linking types, thus tuning the gelation kinetic process of hydrogel formation.

To investigate the rigidity effect, we first prepared DNA supramolecular hydrogel from rigid building block. After hybridization of B-i and cBi at a molar ratio of 1:3 at pH 8.00, the acidic buffer was added to tune the pH to 5.50 and get a final concentration 750 µM for B-i and 2250 µM for cBi. As shown in Fig. 3a, the clear slope appearing in the tube in seconds after pH adjustment indicated the fast gelation process, which was consistent with the quick formation of i-motif.

The rheological tests were then performed to study the properties of this DNA supramolecular hydrogel. As shown in Fig. 3b, the mechanical strength stabilized quickly and the storage modulus (G’, 221.9 Pa) was higher than the loss modulus (G’’, 1.7 Pa), implied a quick gelation process under pH 5.50. The G’ was higher than G’’ over the frequency sweep range (Fig. S5), which was typical behavior of hydrogel. In the oscillatory strain-dependent rheology test (Fig. 3c), G’ of hydrogel decreased rapidly after 40% strain and had a crossing point with G’’ at 80% strain, which implied this hydrogel exhibited a non-Newtonian fluid shear-thinning property. In the temperature mode rheology test (Fig. 3d), with the temperature increased, the G’ decreased and both G’ and G’’ were lower than 10 Pa after 33 ^oC, indicating a gel-sol transition. Hence, the rigid building block could quickly form DNA supramolecular hydrogel with shear-thinning and temperature responsive properties.

Following the same pH adjustment strategy, we also applied flexible building block to prepare DNA supramolecular hydrogel. As shown in Fig. S6, small droplets on the inner wall of the EP tube were observed in the invert-vail test, indicating the system remained in a solution state. Then the solution was incubated at 4 ^oC for 24 h but still no hydrogel was formed. Based on the rigidity difference between B-i and RB, we assumed that the molecular rigidity of building block was critical to gelation and increased rigidity of B-i would facilitate gelation under acid conditions.

Backbone remodeling was then employed to reveal the dynamic effect. After the pH was tuned to 5.50, the cBi was added to increase the rigidity of the flexible building block (B-i). The system gradually lost its fluidity in the invert-vail test and finally formed hydrogel after several hours (Fig. 4a), which was different from the rapid gelation process in the RB. The rheological properties of this DNA supramolecular hydrogel were also studied and the G’ gradually increased from 4 Pa to 120 Pa in about 5 h (Fig. 4b). In subsequent tests, the hydrogel was incubated at 4 ^oC for 24 h after backbone remodeling in order for completely gelation. The mechanical strength of this hydrogel (G’, 211.8 Pa) after incubating was similar to the hydrogel in RB (G’, 221.9 Pa). Furthermore, the same shear-thinning and temperature responsive properties to the RB hydrogel were also confirmed by rheological tests (Fig. 4c, d). These results indicated that compared with the rigid building block, backbone remodeling of the flexible building block would facilitate a slow formation of hydrogel through different microscopic process, but same molecular topological network could be achieved.

To reveal the pathways of the gelation process from different building blocks, we further explored the assembly behavior of B-i and RB at different pH. At pH 5.50, as illustrated in Fig. 5a, large aggregates were formed in the RB sample after pH adjustment (Lane 5), indicating the formation of network assembly. On the other hand, the single band of B-i (Lane 2–4) was observed with slower migration rate than random branched molecule (Sequence can be found in Table S1), which indicated a specific assembly containing at least two B-i was formed. Combined with the CD spectrum of B-i (Fig. 2c), it can be assumed as illustrated in Fig. 1, two adjacent arms in the same molecule formed intramolecular i-motif and the remaining arm formed intermolecular i-motif with another molecule. The backbone remodeling process from the flexible building block to the rigid building block has also been investigated, and as illustrated in Fig. 5a, similar aggregates (Lane 6) were also observed after the introduction of cBi to flexible Bi under pH 5.50 (Lane 5) and subsequent incubation at 4 ^oC for 24 hours, indicating the complete transition from the flexible state to the rigid state.

Based on the above experiments, we put forward the following molecular mechanism: Under acid conditions, for the rigid building block RB, the DNA duplex in the core region could inhibit the intramolecular cyclization and promote the quick formation of intermolecular i-motif network. On the contrary, the flexible building block B-i preferred to form a thermodynamically stable dimer structure (As illustrated in Fig. 1), which cannot form crosslinked hydrogel molecular network. The hybridization of cBi to the flexible B-i under acid conditions could enhance its rigidity, which would potentially break the intramolecular i-motif and subsequently form the intermolecular i-motif network. The stability balance between the i-motif and the duplex played an important role in such backbone remodeling process and therefore, the gelation was a slow process.

To further reveal the mechanism of the ring open process, the pH dependent gelation process has been investigated. With the pH decreased from 6.00 to 5.00, the stability of the intramolecular i-motif was increased (Indicated by melting temperature, summarized in Table S2), which would raise the energy barrier. In the gelation experiments, we found that the RB could still form the hydrogel quickly after pH was adjusting to 5.00 (Rheological properties can be found in Fig. S7). However, the flexible Bi was still in the solution state under same pH even after 24 h at 4 ^oC with the addition of the cBi (Fig. S8), indicating the stable intramolecular i-motif inhibits the ring open. Native PAGE also supported the conclusion and under pH 5.00 (Fig. 5b), no larger assembly was formed after 24h (Lane 7) while most dimer were still kept after 10 days (Lane 6). On the other hand, when pH was tuned to 6.00, the flexible Bi could form the hydrogel about 4 h after the addition of cBi (Fig. S9), which can be explained by the higher stability of the duplex than the i-motif. It should be noted that due to the low stability of i-motif, the hydrogel can’t be maintained at room temperature under pH 6.00, which was consistent with the rigid system (Fig. S10). However, the relative faster gelation speed under pH 6.00 (< 4 h) than pH 5.50 (~ 5 h) at 4 ^oC could still support the ring open mechanism. These results demonstrated the important role of the energy barrier in opening ring, and further indicated the importance of the rigidity of the building blocks.

The molecular network of the hydrogel rigidity was also tuned in situ through strand displacement (Fig. 6a). We have prepared a Lc sequence, which extended a toehold to cBi (Sequence can be found in Table S1). As illustrated in Fig. 6b, this Lc -RB could also form the molecular network (Lane 4) and the hydrogel (Fig. S11). Then a Fuel strand (Fully complementary to Lc, Table S1) was added to remove the Lc from network to change its rigidity at 4°C for 24 h. To demonstrate the successful strand displacement, fluorescence labeled Lc was applied and analyzed by the native PAGE. After the incubation, we found that the aggregates still existed (Fig. 6b, Lane 5) but no fluorescence signal could be observed in the sample well under the fluorescence imaging (Fig. 6c, Lane 3). We found that after the strand displacement, the hydrogel state was still maintained (Fig. S11), which indicated that the hydrogel network would not collapse even Lc was completely removed. We have also applied rheological test to investigate the properties of the hydrogel after strand displacement. As shown in Fig. 6d and 6e, the G’ decreased from 1230 Pa to 443.7 Pa and the gel-sol transition point increased from 18.0–55.4% during strain sweep after backbone remodeling. These results proved that the flexible network was thermal stable and gelation was kinetically controlled by the ring open process. Our strategy has also allowed to prepare hydrogel with the both rigid and flexible network, which determines the rheological properties of the hydrogel.

In summary, the rigidity effect of the building blocks in the formation process of DNA hydrogel has been investigated. Through tuning the hybridization state, the rigidity of the branched DNA molecule has been adjusted and the different gelation pathways have been revealed between the rigid and flexible building block systems. It has been observed that high rigidity could inhibit the intramolecular cyclization of the branched molecule and promote the quick formation of hydrogel network. The energy barrier of the ring open process can be affected by the stability balance between the rigid and flexible states of the building block, which therefore plays a fundamental role in determining the backbone remodeling process. We also proved that the molecular network could be still maintained after the building block was adjusted to the flexible state, which further demonstrated the gelation is kinetically controlled by the ring open process. It can be anticipated that our results could further deepen the understanding of the relationship between the building block rigidity and gelation process, which would expand the application of DNA hydrogels in biomimetic materials and smart devices.

Materials

Acrylamide, N,N-methylene bis-acrylamide, ammonium persulphate (APS), ammonium hydroxide (NH₃•H₂O), 2-morpholineethanesulfonic acid (MES), trifluoroacetic acid, sodium chloride (NaCl), tris(hydroxymethyl)-aminomethane (Tris), ethylenediaminetetraacetic acid disodium salt (EDTA•2Na), boric acid (B(OH)₃), hydrochloric acid (HCl), sodium hydroxide (NaOH), triethylamine, acetic acid were purchased from Sigma-Aldrich. Branched phosphonamidite Long Trebler was purchased from Glen research. All reagents used for DNA solid-phase synthesis (CPG, four phosphoramidite monomers, oxidant, activator, acetonitrile, Cap A, Cap B) were purchased from Hebei Dinaxingke (China). 0.22 µm polyether sulfone filter membrane was purchased from Millipore.

DNA synthesis

All the molecules were synthesized by a Mermade 12 DNA synthesizer (Bioautomation Company) using commercially available phosphonamidites and CPG in 1 µmol scale. For the synthesis of B-i, the coupling time of Long Trebler (purchased from Glen research) with was increased to 15 minutes. After the synthesis, the CPG loaded with oligonucleotides was placed in concentrated ammonium hydroxide and heated at 60 ^oC for 3 hours to cleave the DNA from CPG. Then the oligonucleotides were purified by RP-HPLC (Agilent Technologies) using acetonitrile and triethylammonium acetate buffer as elution. The purified oligonucleotides were treated with trifluoroacetic acid to remove DMT group at 5’ end and remove salts by ultrafiltration. All synthesized DNA molecules were characterized by 20% denaturing PAGE and MALDI-TOF (Shimadazu Biotech Axima Performance).

Polyacrylamide Gel Electrophoresis (PAGE) analysis

The 20% denaturing PAGE (Acrylamide: Bis-acrylamide = 19:1, 7 M Urea) was used to characterize the synthesis of oligonucleotides with 1× TBE (Tris-B(OH)₃-EDTA•2Na) as running buffer. And for the analysis of the assembly behavior, the pH 8.00 10% native PAGE (Acrylamide: Bis-acrylamide = 19: 1) with 1× TBE as running buffer and the pH 5.00/5.50 10% native PAGE with MES buffer (50 mM MES and 12.5 mM MgAc₂) as running buffer were performed at 4 ^oC. For the fluorescence native PAGE, 2% FAM-modified Lc was added.

Circular dichroism (CD) spectrum measurement

The oligonucleotides were dissolved in MES buffer (50mM MES and 137 mM NaCl) at different pH, then the samples were heated to 95 ^oC for 5 minutes and cooled to room temperature gently. The circular dichroism spectrum of the sample in the wavelength range of 225 nm to 320 nm was collected by Applied Photophysics Chirascan Spectropolarimeter at room temperature in a 1.0 cm sample cell. Each sample was measured three times and averaged. The scan of the buffer alone was used as a control and subtracted from the average scan for each sample.

Melting point measurement

The melting profile of the i-motif was measured by Applied Photophysics Chirascan Spectropolarimeter. The temperature was scanned from 5 ^oC to 90 ^oC at a scan rate of 1 ℃/min. For both B-i and I the CD signal at 282 nm was detected. The melting profile of the DNA duplex was measured by ultraviolet and visible (UV-Vis) spectrophotometer (Agilent Cary 100) and the absorbance at 260 nm was detected. The cell length was 1.0 cm in all measurements. And the melting point (Tm) was obtained from the peak of the corresponding differential melting curve.

Preparation of DNA supramolecular hydrogels.

For rigid building block, both B-i and cBi were first dissolved in pH 8.00 MES buffer (5 mM MES and 137 mM NaCl) and heated to 95 ^oC for 5 min and cooled to room temperature naturally. Then 500 mM MES buffer (pH = 5.00/5.50/6.00) was added to the sample to tune the buffer to acidic with a final MES concentration was 50 mM. The final concentration of B-i was 750 µM and cBi was 2250 µM.

For flexible building block, B-i was dissolved in an acidic MES buffer (50 mM MES and 137 mM NaCl, pH = 5.00/5.50/6.00) directly and further incubated at 4 ^oC for 24 h. The concentration of B-i was 750 µM.

For backbone remodeling process, both B-i and cBi were individually dissolved in an acidic MES buffer (50 mM MES and 137 mM NaCl, pH = 5.00/5.50/6.00) to reach a concentration of 1.5 mM for B-i and 4.5 mM for cBi. Then these 2 solutions were mixed in equal volume and incubated in 4 ^oC for 24 h to form the DNA hydrogel. The final concentration of B-i was 750 µM and cBi was 2250 µM.

For in situ tuning rigidity of hydrogel molecular network through strand displacement, both B-i and Lc were first dissolved in pH 8.00 MES buffer (5 mM MES and 137 mM NaCl) and heated to 95 ^oC for 5 min and cooled to room temperature naturally. Then 500 mM MES buffer (pH = 5.00/5.50/6.00) was added to the sample to tune the buffer to acidic with a final MES concentration was 50mM. After 24 h incubation at 4 ^oC, Fuel equal to Lc was added and further incubated at 4 ^oC for another 24 h to ensure a completely strand displacement. The final concentration was 750 µM for B-i and 2250 µM for Lc and Fuel.

Rheological tests

A Kinexus Pro + rheometer (Malvern Instruments) was used to test the rheological properties of the formed DNA hydrogels in the following mode: (i) Time sweep test was carried out at a fixed strain of 1% and frequency of 1 Hz at 25 ^oC for 5 min. (ii) Strain sweep tests were carried out from 0.1 to 100% with a fixed frequency of 1 Hz at 25°C; (iii) frequency sweep was performed from 10 to 0.01 Hz with a strain of 1%. (iv) temperature tests were performed at a frequency of 1 Hz, a strain of 1%, with different temperature range and heating rate of 1 ^oC /min.

Acknowledgement

This work was supported by Institute of Chemistry CAS (C220200701), National Natural Science Foundation of China (21890731, 21821001, 21534007, 21971248, 21890730), National Basic Research Plan of China (2018YFA0208900) for financial support.

Author details

¹Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China.

²CAS Key Laboratory of Colloid Interface and Chemical Thermodynamics, Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.

³University of Chinese Academy of Sciences, Beijing 100049, P.R. China

Author contributions

D.L. and Y.D. conceived the idea and designed the experiment. Y.P. and B.Y. conducted the experiments and data analysis. Y.P. wrote the manuscript. R.X., X.L., Y.D., and D.L. assisted with the writing of the manuscript.

Conflict of interest

The authors declare no competing interests.

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Rigidity dependent formation process of DNA supramolecular hydrogel

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