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Host-guest assembly triggered lower critical solution temperature behavior with

reversible photo-regulation

Zhuoran Xu, Xiujun Liu, Tao Jiang, Xiang Ma

PII: S0143-7208(24)00016-0
DOI: https://doi.org/10.1016/j.dyepig.2024.111951
Reference: DYPI 111951

To appear in: Dyes and Pigments

Received Date: 13 November 2023

Revised Date: 5 January 2024
Accepted Date: 5 January 2024

Please cite this article as: Xu Z, Liu X, Jiang T, Ma X, Host-guest assembly triggered lower critical
solution temperature behavior with reversible photo-regulation, Dyes and Pigments (2024), doi: https://
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Graphical Abstract

Host-Guest assembly triggered lower critical solution temperature

behavior with reversible photo-regulation
Zhuoran Xu, Xiujun Liu, Tao Jiang* and Xiang Ma
Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and
Molecular Engineering, East China University of Science and Technology, Meilong Road 130, Shanghai 200237 (P. R. China).

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A tunable LCST behavior triggered by host-guest recognition

Host-Guest assembly triggered lower critical solution temperature

behavior with reversible photo-regulation

Zhuoran Xu, Xiujun Liu, Tao Jiang* and Xiang Ma

Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center,
School of Chemistry and Molecular Engineering
East China University of Science and Technology
Meilong Road 130, Shanghai 200237 (P. R. China).

Abstract

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The less frequent lower critical solution temperature (LCST) phenomenon has attracted extensive

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attention due to the foresighted application in smart materials. Nevertheless, the existing LCST-type
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materials are mainly dominated by a few polymers with specific moieties due to the damped
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hydration at a higher temperature and the lack of reversible regulations of the corresponding
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temperature sensitivity. Herein, an unanticipated and reversibly photo-responsive LCST behavior

was uncovered in the BSC4/Azo-4 assembly solution. Such behavior arose from the host-guest
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binding between BSC4 and Azo-4 in an aqueous solution since neither the guest nor host alone

exhibited an LCST property. Ascribing to the distinct π-π stacking between the trans- and cis-

isomers of Azo-4, a reversible regulation of LCST behavior was achieved by irradiating UV and

blue light alternately. Our study demonstrated the complexity and possibility of supramolecular self-

assembly, opening a new avenue in the fabrication and adjustment of LCST-type materials in the

future.

Keywords: Lower Critical Solution Temperature; Stimulus Responsive System; Supramolecular

*Corresponding author.
E-mail address: sailing_072@163.com
Assembly; Host-Guest Assembly

Introduction

Dynamically controlled supramolecular self-assembly has attracted extensive attention in light of

its vast potential applications in drug delivery, phase transfer catalysis, optic sensing, and bio-

medicine, and widely exists in organism activities [1-9]. The susceptibility to external stimuli, such

as light, electric fields, pH, and temperature is the key to accessing the dynamical controllability of

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dynamically controlled self-assembly [10-13]. In particular, aqueous phase temperature-sensitive

self-assembly has been a research emphasis due to the practicality and foresight in bio-materials,

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phase-transfer catalysis, and smart surface [14,15]. In this case, two opposite types of temperature-
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depended physical properties have been addressed, that is, an upper critical solution temperature
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(UCST) and a lower critical solution temperature (LCST). As a less frequent phase-separate
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behavior, LCST depicts an immiscible phenomenon in solution and blends instead when
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temperature increases. The recent LCST-type materials are mainly focused on partial ionic liquids
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[16-18] and polymers with specific moieties, such as poly N-isopropyl acrylamide (PNIPAM), oligo

ethylene glycols (OEGs), poly N-vinyl caprolactam (PVCL) [19-23]. The prevailing insight to the

LCST-type polymers is the damped hydration continuously with elevated temperature ascribing to

the break of hydrogen bonds between water molecules and the corresponding moieties on the

polymers, resulting in a stretched to the coiled transformation of polymer chains and heterogeneous

turbid solution at the macroscopic level [24,25]. Eventually, this alteration of macroscopic property

derived from molecular-level change is of significance to understanding the denaturation of proteins

undergoing heat and cold treatments [26].

Unfortunately, only a few types of polymers dominate current temperature-sensitive materials

although the LCST-type materials are increasingly developed in recent years. As mentioned above,

the prevailing building blocks are mainly concentrated in PNIPAM and OEGs moieties to achieve

a thermal-sensitivity, and the alternative LCST groups are rather rare so far. Besides, the adjustment

to the critical temperature of LCST commonly depends on the doping content of thermally-sensitive

building blocks or the modification of additional hydrophobic and hydrophilic groups. These

statuses have limited the molecular design of thermally-sensitive materials, especially for those

small molecules. In this regard, throwing a sight on supramolecular self-assembly may provide an

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alternative strategy to fabricate small-molecule LCST systems [27,28]. More is different [29], it is

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a great challenge to accurately predict the emerging macroscopic properties of self-assembling
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systems which are frequently involved in multiple supramolecular interactions. On the other hand,
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the complexity of supramolecular assemblies can probably enable assembled molecules with

unexpected additional properties [30-33].

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In our previous work, an unexpected LCST behavior of supramolecular self-assembly was

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uncovered by a host-guest recognition between a bromonaphthol derivative and host BSC4 (Bis-p-
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sulfonatocalix[4]arene) in aqueous solution [34]. Notably, neither the free guest nor BSC4 showed

any LCST behavior before host-guest inclusion. The emerging behavior inspires us to explore other

potential LCST candidates. However, due to the unsettled mechanism of the emerging thermal

sensitivity, any minor modifications to the structure of host or guest molecules would lead to the

disappearance of the LCST phenomenon of the assemblies, let alone the corresponding adjustment

and functionalization. To this end, herein, we designed an Azo-4 guest based on azobenzene

modified with a quaternary ammonium terminal alkyl chain to assemble with BSC4. Temperature-

depended NMR, morphological analysis, and calorimetric titration showed a tiny variation of
inclusion between Azo-4 and BSC4 with temperature could remarkably affect the packing pattern

of azobenzene units and the hydration of Azo-4/BSC4 self-assembly, which was the critical

contribution to the resulting LCST behavior. Moreover, the excellent photo-isomerization ability of

Azo-4 endowed our LCST supramolecular system with a reversible light responsibility, providing

the feasibility of developing functional thermally-sensitive materials by host-guest strategy.

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Fig. 1. a) Schematic illustration of the LCST process of BSC4/Azo-4 complex by supramolecular interaction. b)
Temperature-dependence of transmittance of the LCST sample. c) Photographs of BSC4/Azo-4 = 1/1 solution at
different temperatures. TEM pictures of BSC4/Azo-4 = 1/1 solutions at different temperatures. d-e) 10°C; f-i) 40°C
(BSC4/Azo-4 = 2.5 mM). Scale Bar: d: 0.5 μm; f: 1 μm; h: 0.5 μm; e: 0.2 μm; g: 2 μm; i: 0.2 μm.

As a classical photo-isomeric group, the azo-unit has been widely used in various photo-

responsive assembly systems due to their excellent isomeric performance [35-37]. The synthetic

route and structural characterization of the Azo-4 (default to trans-configuration if no special

annotations are made) were shown in Scheme S1. As shown in Figure 1, the quaternary unit of the

Azo-4 can interact strongly with the poly-anion macro-cyclic of BSC4, resulting in site-specific
recognition of the encapsulation at the cavity of BSC4. As shown in Figure S1, when 1.0 eq of

BSC4 was added, the chemical shifts of all protons (f-j) in the alkyl quaternary region on Azo-4

were significantly shifted upfield due to the shielding effect of the BSC4 cavity. And the aromatic

protons (a-e) of Azo-4 also shifted upfield slightly, resulting from the π-π stacking interaction

between the azo-unit and calixarene-induced aggregation (CIA) effect [38-41]. In addition, as

shown in Figure S3, only one significant NOE signal between the protons (l) on the aromatic ring

of BSC4 and the protons (j) of the methyl group on the quaternary ammonium unit of Azo-4 is

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recorded, demonstrating that the quaternary ammonium terminal rather than Azo-unit is the

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inclusion site of Azo-4 due to the rather shallow cavity of BSC4 comparing to other typical hosts
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such as cyclodextrins. Besides, ITC measurement demonstrated that BSC4 and Azo-4 adopted a
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ratio of 1:2 inclusion pattern in an aqueous solution with a large binding constant of 3.24×104 M-2

(Figure S2), and the thermodynamic information also demonstrated that the host-guest binding
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between BSC4 and Azo-4 is an enthalpy driven process, which mainly derives from the Coulombic
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effect between poly-anion of BSC4 and the positively charged quaternary ammonium unit.
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UV-Vis absorption spectra further verified the host-guest interaction between Azo-4 and BSC4

and the self-assembly of supra-amphiphilic BSC4/Azo-4 (Figure S4). When the equivalent of BSC4

was less than 0.5 eq, the absorption at 345 nm kept decreasing, but with further addition of BSC4,

the absorbance at 345 nm showed a certain degree of increase instead. This unusual phenomenon is

due to the combined effect of the host-guest encapsulation and CIA of BSC4. With the subsequent

addition of BSC4, the assembly mode turns to 1:1 rather than the original 1:2, thus weakening the

aggregation of BSC4/Azo-4 assemblies due to the large hydrophily and charge repulsion of BSC4.

This is also evidenced by the photograph of turbidity-clarification transformation in Figure S5.

Transmission Electron Microscope (TEM) of BSC4/Azo-4 at different ratios (10°C) were

conducted to reveal the microscopic morphological changes (Figure S6-7). The aqueous solution of

Azo-4 showed a planar structure in TEM; when 0.5 eq of BSC4 was added, the morphology was

transformed into a cross-linking of sphere/membrane hybrid (Figure S6b-c); for the case of

BSC4/Azo-4 =1/1, the large cross-linked structures were further converted into spherical

nanoparticles with a size below 200 nm (Figure S6d). This morphological variation illustrates that

the over-equivalent BSC4 can effectively prohibit the formation of large self-assembled

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nanostructures.

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Both Azo-4 and BSC4 exhibited profound solubility in water especially at high temperatures.
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However, the Azo-4 /BSC4 =1/1 assembly solution showed significant turbidity at 35°C, and turned
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to the clarified state perversely with decreasing temperature below 10°C (Figure 1a,1c). As shown

in Figure 1c, the yellow limpid solution gradually evolved into a heterogeneous system when
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temperature was increased. Accordingly, the word “LCST” on the background plate turned out to
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be invisible. Instead, such turbid solution could be clear again when the temperature turned back to
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10°C. Meanwhile, the transmittance curve also showed a remarkable change in the range of 18°C-

30°C and the Tcloud was approximately at 24°C (Figure 1b). To reveal the microscopic changes d,

TEM photographs of BSC4/Azo-4 =1:1 solution at different temperatures were investigated. At a

low temperature (10°C), the system exhibited spherical nanoparticles with diameters less than 200

nm (Figure 1d-e); when the temperature raised to 40°C, extensive cross-linking nanostructures were

formed between the original spherical nanoparticles resulting in forming irregular structures with

sizes above 1 μm (Figure 1f-i). It is reasonable to speculate that the temperature-induced

microscopic cross-link eventually leads to a macroscopic phase transformation. Temperature

dependent dynamic light scattering (DLS) and zeta potential study also indicated that the change of

the hydrodynamic size during this process, and the results are consistent with TEM (Figure S8, S9).

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Fig. 2. a) Schematic diagram of photo-isomerization of Azo-4. b) The photographs of the LCST sample under
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continuous irradiation by 365/430 nm light in sequence. c) Alteration of transmittance of the LCST sample under
periodic irradiation by 365 nm and 430 nm light in sequence. All measurement processes were carried out at 30°C.
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The above results showed that slight changes in molecular structure would result in a dramatic
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effect in supramolecular self-assembly. As an excellent photo-isomeric group, the azo-unit's steric

hindrance, molecular planarity, and dipole change significantly upon irradiation (Figure 2a, S10).

Therefore, the isomerization may exert a considerable impact on the LCST behavior. As shown in

Figure 2, the turbid BSC4/Azo-4 (1/1) solution gradually evolved to a clarified one under

continuous irradiation of 365 nm light at 30°C and stayed transparent even at a higher temperature.

Conversely, the clarified solution would eventually return to the initial turbid state upon 430 nm

light irradiation and maintain the switch thoroughly after 25 cycles of irradiation owing to the

efficient photo-isomerization of Azo-4 (Figure 2c). Additionally, morphological analysis by TEM

addressed a dissociation of BSC4/Azo-4 self-assembled nanostructures when Azo-4 was in cis-

configuration. As shown in Figure S12, the morphologies of the Azo-4 monomer and BSC4/Azo-4

assemblies underwent significant dissociation after 365 nm light irradiation compared with those in

Figure S6-7. We deduce that the inter-aromatic π-π stacking is severely inhibited when trans-Azo-

4 transforms into cis-configuration and the increased dipole moment of cis-Azo-4 favors the

hydration. Due to the two factors, the aggregation of BSC4/Azo-4 = 1:1 is impaired as the result of

the turbid-to-clarified process under irradiation.

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As shown in Figure S10, the upfield shift of protons (a’-e’) on the Azo-unit changes a little

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after host-guest inclusion, indicating that the π-π stacking between trans-Azo-4 is larger than cis-
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Azo-4 after being included by BSC4. In comparison, the chemical shifts of protons on the alkyl
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chain of cis-Azo-4 (f’-j’) present a remarkable upfield shift. This difference may result from the

aggregation of trans-Azo-4. For the case of cis-Azo-4, the less planarity limited the π-π stacking
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and impeded the aggregation of BSC4/cis-Azo-4; on the other hand, BSC4/trans-Azo-4 presented
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apparent aggregation at a high concentration due to the well-stacking behaviour and hydrophobicity
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of trans-Azo-4. However, the π-π stacking of trans-Azo-4 contradicted the steric hindrance of

BSC4 upon host-guest recognition, resulting in a shallower inclusion between the chain terminal of

trans-Azo-4 and the cavity of BSC4. Notably, the compromise of the two factors is crucial to the

explanation for LCST behavior in below.

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Fig. 3. Schematic of temperature-dependent self-assembly of BSC4/Azo-4.
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The plausible mechanism has been investigated by temperature-dependent 1H NMR study. As
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shown in Figure S13 and S14, when the temperature was increased up to 50°C, the chemical shift

of the aromatic ring and the nearby protons (a-f) on BSC4/trans-Azo-4 significantly shifted
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downfield; instead, the signals of terminal protons (g-j) on the alkyl chain shifted upfield. Especially,
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a split and upfield-shifted NMR signal of the terminal proton j was observed evidently, indicating
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a deeper encapsulation between BSC4 and Azo-4. In comparison, the signals of BSC4/cis-Azo-4

protons (red letter) merely changed a little. Considering the remarkable aggregation distinction

between trans- and cis-Azo-4, it is reasonable to deduce that the efficient π-π stacking of Azo-4

limits the encapsulation of BSC4 resulting in a superficial binding; in turn, the large steric hindrance

and coulomb repulsion of BSC4 impedes the slide face-to-face stacking between azo-units, thus

leading to a V-shape stacking motif. There are two shreds of evidence to support this speculation: i)

the curved super-amphiphilic stacking favors to form spherical nanoparticles as addressed by TEM

and ii) the chemical shift of protons a and b shifts more upfield than that of the others on the azo-
unit since the closer distance between the head of Azo-4. The increased temperature induces a

disruption of the V-shape stacking to promote a deeper encapsulation and a parallel style for

BSC4/Azo-4 self-assembly, which results in a less ratio of hydrophilic/hydrophobic volume and

presents a large-size fused nanoparticles as demonstrated in TEM (see Figure 3).

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Fig. 4. Dilution enthalpy traces of BSC4/Azo-4 (=1/1) solution titrated into pure water examined by ITC at 298 K
a) before and b) after 365 nm light irradiation.

Besides, the dilution enthalpy of concentrated BSC4/Azo-4 solution before and after

irradiation was examined by an ITC study. As shown in Figure 4, both isomeric BSC4/Azo-4

assemblies exhibit an exothermic effect when diluted in water, demonstrating the existence of

hydration. Nevertheless, the trans-BSC4/Azo-4 presents a gradually saturated heat release

compared with the cis-counterpart, indicating a considerable aggregation when the concentration

approximately exceeds 0.3 mM. This exothermic effect also suggests that the hydration of
BSC4/Azo-4 self-assembly at high concentrations will probably be suppressed if the temperature

rises. As a result, a turbid solution can be obtained from a clear one when heated up to a certain

temperature.

In summary, we successfully constructed a supramolecular self-assembly system with dual

stimulation response to temperature and light through a host-guest assembly process between an

alkyl quaternary ammonium-modified azobenzene guest molecule and the host BSC4. Notably, at

a BSC4/Azo-4 = 1:1 mixing ratio, the assembled solution (2.5 mM) exhibits an unexpected LCST

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behavior at the Tcould of 24°C, which was unsuspected in both the Azo-4 solution and the BSC4

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solution. A series of systematic characterizations suggest that this unanticipated LCST behavior
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arises from the delicate compromise of the different intermolecular interactions, and the exothermic
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hydration effect. This assembly equilibrium is highly susceptible to perturbation by subtle changes

in external temperature and intermolecular stacking, thus exhibiting the LCST phenomenon in
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response to photo-stimulation. This work aims to demonstrate the potential and value of supra-
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amphiphilic assemblies in functional materials. It is expected that this strategy will play an essential
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guideline in the field of thermal-responsive materials in the future.

Acknowledgments

This work was supported by the National Key Research and Development Program of China

(2022YFB3203500), the National Natural Science Foundation of China (22125803, 22108078, and

22101083), and the China Postdoctoral Science Foundation (No. 2021M691009).

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Supplementary Material

Supplementary material that may be helpful in the review process should be prepared and

provided as a separate electronic file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the appropriate editorial office.

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Research Highlights of this work are including:

1. A remarkable LCST behavior was observed in this supramolecular amphiphilic

system without any LCST-type groups. Notably, neither Azo-4 nor BSC4 alone
presented a predictable LCST property.

2. The work demonstrated that the compromise of multiple non-covalent

interactions and the exothermic hydration effect triggered a subtle change of
BSC4/Azo-4 complexes, resulting in a considerably different microscopic
morphology that played a critical role in the emergency of LCST property.

3. The distinct π-π stacking between the trans- and cis- isomers of Azo-4 gave

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rising to a reversible regulation of the LCST behavior by irradiating UV and blue

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light alternately.

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Conflicts of interest
All authors disclosed no relevant relationships.

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