Multi-response microgel with ultrathin shell layer and preparation method of multi-response microgel

Abstract

The invention discloses multi-response microgel with an ultrathin shell layer and a preparation method of the multi-response microgel, and relates to the technical field of gel. The preparation method comprises the following steps: preparing an inner oil phase, a middle water phase and an outer oil phase; respectively injecting the inner oil phase, the intermediate water phase and the outer oil phase into a microfluidic device to obtain O / G / O type double emulsion microgel; and carrying out a cross-linking reaction on the double emulsion and a cross-linking agent, thereby obtaining the product. According to the preparation method disclosed by the invention, the O / G / O type double-emulsion microgel with a core-shell structure is successfully prepared by taking corn oil, gelatin and sodium alginate as main raw materials by adopting a micro-fluidic technology, so that the embedding rate of a target object can be improved, and active adsorption and embedding of active substances are realized; the emulsion microgel is further subjected to cross-linking modification, through cross-linking modification, the stability and strength of the O / G / O type double emulsion microgel structure after swelling adsorption are improved, the shell layer of the microgel is converted into a nano-scale thin film from a micron-scale thin film, and the multi-response microgel with an ultrathin shell layer is formed.

Description

Technical Field

[0001] This invention relates to the field of gel technology, specifically to a multi-responsive microgel with an ultrathin shell and its preparation method. Background Technology

[0002] Precise delivery and controlled release of natural active ingredients are research hotspots in the food, pharmaceutical, and cosmetic fields. As functional carriers, microgels, with their unique three-dimensional network structure and environmental interaction characteristics, can achieve controlled absorption and release of solvents through reversible swelling and contraction behavior, demonstrating significant advantages in protecting active ingredients, maintaining structural stability, and regulating release kinetics. However, the complex environment of food matrices (such as mechanical shear, temperature fluctuations, and changes in ionic strength) often leads to structural instability of delivery systems or premature release of contents, limiting their application effectiveness in antibacterial preservation, nutrient fortification, and targeted delivery scenarios. Therefore, developing food-grade microgel carriers with stable environmental adaptability and controllable encapsulation and release performance has become a crucial issue that urgently needs to be addressed.

[0003] Microgels, as one of the important carriers for delivering bioactive ingredients, have shown broad application prospects in the fields of food, biomedicine and cosmetics. In the food industry, encapsulation delivery systems based on microgel network structures can achieve precise controlled release of various functional components: bioactive peptides (such as glutathione and nisin) can be delivered using micro / nano-scale encapsulation technology, effectively maintaining their structural stability and bioactivity; for lipid-soluble functional components (such as β-carotene) and polyphenols and flavonoids (such as quercetin), multi-level delivery systems constructed through interface engineering can significantly improve their bioavailability and achieve targeted release of the carrier in the human gastrointestinal tract or colon; furthermore, by designing the stimulus-responsiveness of microgel carriers, the synergistic release of antioxidants such as vitamin E and natural antibacterial agents can be achieved, extending the shelf life of food while inhibiting the proliferation of foodborne pathogens. Current research both domestically and internationally focuses on improving carrier stability and constructing functional carriers based on structural design to enhance the functional properties and bioavailability of encapsulated substances. Although microgel carriers have shown significant advantages in improving the bioaccessibility and stability of encapsulated materials, their response accuracy in dynamic delivery scenarios still needs improvement, posing a new demand for the development of intelligent delivery systems with environmental responsiveness.

[0004] Existing responsive microgel delivery carriers include single-response carriers such as pH-responsive carriers, heat-responsive carriers, and enzyme-responsive carriers. While there is considerable research on single-stimuli-responsive microgels, practical applications of these delivery systems often require handling complex and variable environments. Therefore, microgel systems with dual or even triple stimulus-responsive properties are becoming a research hotspot. Zhao Hui's team used a nonionic surfactant, carboxymethyl cellulose, from Tremella fuciformis polysaccharide as a matrix and constructed a pH / temperature dual-responsive hydrogel via free radical polymerization, successfully achieving the controlled release of hydrophobic drugs. Liao Jian innovatively used Hericium erinaceus residue as raw material to synthesize Fe3O4 nanoparticles in situ within a carboxymethyl chitin hydrogel matrix, developing a pH / magnetic dual-sensitive smart hydrogel. This system allows for precise adjustment of the hydrogel's swelling degree and responsiveness by regulating the Fe3O4 content, and the loaded 5-fluorouracil exhibited pH-dependent release behavior in in vitro experiments. The significant differences in pH, temperature, and enzyme conditions in the human gastrointestinal tract provide a reference for designing multi-responsive microgel delivery systems. When a delivery system traverses the digestive tract, changes in the pH of the surrounding aqueous phase can alter the charge state of microgel components (surfactants, proteins, polysaccharides, etc.), leading to network restructuring and interaction reconfiguration. Simultaneously, temperature changes during food intake and digestion can trigger physical phase transitions and affect the digestive kinetics of key components. Traditional techniques for designing and preparing multi-responsive carriers often suffer from problems such as poor carrier response sensitivity and unstable controlled release due to low precision in network structure design and rudimentary processes. Summary of the Invention

[0005] The purpose of this invention is to at least solve one of the technical problems existing in the prior art, and to provide a multi-responsive microgel with an ultrathin shell and its preparation method.

[0006] The technical solution of the present invention is as follows: In a first aspect, the present invention provides a method for preparing multi-responsive microgels with an ultrathin shell, comprising the following steps: S1. Prepare the internal oil phase, intermediate aqueous phase, and external oil phase; S2. The inner oil phase, the intermediate aqueous phase and the outer oil phase are injected into a microfluidic device to prepare an O / G / O type dual emulsion microgel. S3. The O / G / O type dual emulsion microgel is subjected to a crosslinking reaction with a solution containing a crosslinking agent to obtain a multi-response microgel with an ultrathin shell.

[0007] Optionally, in S1, the inner oil phase includes corn oil and polyglycerol ricinoleate, the intermediate aqueous phase includes gelatin, sodium alginate and water, and the outer oil phase includes corn oil and polyglycerol ricinoleate. The volume ratio of the inner oil phase, the intermediate aqueous phase and the outer oil phase is 1:3~5:9~11.

[0008] Optionally, in S1, the amount of polyglycerol ricinoleate added in the inner oil phase is 0.5-1.5 wt% of corn oil; the amount of gelatin added in the intermediate aqueous phase is 9-11 wt% of water; the amount of sodium alginate added is 0.5-5 wt% of water; and the amount of polyglycerol ricinoleate added in the outer oil phase is 2.5-3.5 wt% of corn oil.

[0009] Optionally, in S2, the microfluidic device includes a first raw material tube, a second raw material tube, and a third raw material tube. The first raw material tube is connected to one end of the second and third raw material tubes, and an inner oil phase inlet is provided at the connection point. The other end of the first, second, and third raw material tubes each has an outlet. Along the direction from the inner oil phase inlet to the outlet, the first, second, and third raw material tubes are each provided with an intermediate aqueous phase inlet and an outer oil phase inlet in sequence.

[0010] Optionally, in S2, the inner oil phase, the intermediate aqueous phase, and the outer oil phase are injected into the microfluidic device at 55~65°C, respectively. The flow rate of the inner oil phase injected into the microfluidic device is 600~1000 μL / h, the flow rate of the intermediate aqueous phase injected into the microfluidic device is 2700~3700 μL / h, and the flow rate of the outer oil phase injected into the microfluidic device is 7500~8500 μL / h.

[0011] Optionally, in S3, the crosslinking agent in the solution containing the crosslinking agent is at least one of zinc sulfate, epigallocatechin gallate, and glutaraldehyde, and the volume ratio of the O / G / O type dual emulsion microgel to the solution containing the crosslinking agent is 1:4~6.

[0012] Optionally, the solution containing zinc sulfate has a mass concentration of 0.5-1.5%, the solution containing epigallocatechin gallate has a concentration of 4-6 mg / ml, and the solution containing glutaraldehyde has a mass concentration of 2-3%.

[0013] Optionally, S3 includes the following steps: The O / G / O type dual emulsion microgel was washed and then dispersed in a solution containing the target embedding material and soaked for 10-30 min until it swelled to a stable volume to obtain a dispersion system; wherein, the solution containing the target embedding material contains macromolecular proteins and / or nanoparticles and / or small molecule active peptides and / or small drug molecules. Then crosslinking is performed according to one of steps (1)-(3): (1) The dispersion system is added to crosslinking agent 1 and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a multi-response microgel with an ultrathin shell. (2) Add the dispersion system to crosslinking agent 1, crosslink fully, and rinse with pure water after crosslinking to obtain an aqueous dispersion system; add crosslinking agent 2 to the aqueous dispersion system, crosslink fully, and rinse with pure water after crosslinking to obtain a multi-response microgel with an ultrathin shell; (3) The dispersion system is added to crosslinking agent 1 and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a first aqueous dispersion system. Crosslinking agent 2 is added to the first aqueous dispersion system and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a second aqueous dispersion system. Crosslinking agent 3 is added to the second aqueous dispersion system and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a multi-response microgel with an ultrathin shell. Wherein, crosslinking agent 1, crosslinking agent 2 and crosslinking agent 3 are respectively one of zinc sulfate, epigallocatechin gallate, and glutaraldehyde.

[0014] Secondly, the present invention provides a multi-responsive microgel with an ultrathin shell, which is obtained by the preparation method described above.

[0015] Thirdly, the present invention provides a multi-response microgel with an ultrathin shell, wherein the multi-response microgel with an ultrathin shell comprises an inner core and a shell, wherein the thickness of the shell is less than 300 nm.

[0016] This invention has at least one of the following beneficial effects: First, this invention utilizes microfluidic technology to successfully prepare an O / G / O type dual emulsion microgel with a core-shell structure using corn oil, gelatin, and sodium alginate as the main raw materials. Specifically, this invention uses gelatin and sodium alginate together as the aqueous phase. Gelatin and sodium alginate form a stable semi-interpenetrating network structure through hydrogen bonding and electrostatic interactions, significantly altering the shell swelling behavior. The flexible carboxylate groups of the sodium alginate molecular chains insert into the triple helix network of gelatin, forming a more open porous structure. Furthermore, a certain amount of interstitial space is generated after swelling, which can be applied to drug delivery, microresponse devices, and microsensor design. Therefore, the above method helps to improve the swelling adsorption of target solutions, i.e., improve the encapsulation rate of target substances, and achieve active adsorption, encapsulation, and protection of active substances.

[0017] Secondly, this invention further crosslinks the O / G / O type dual emulsion microgel with a core-shell structure after swelling and adsorption. This crosslinking modification not only improves the stability and strength of the dual emulsion microgel structure after swelling and adsorption, but also transforms the shell of the microgel from micrometer-scale to nanometer-scale thin, forming a multi-responsive microgel with an ultrathin shell. Specifically, Zn 2+The carboxylate group of sodium alginate forms an "egg-box" structure through ionic bonds, increasing the crosslinking density and causing the polymer network to shrink. Epigallocatechin gallate, due to its abundant phenolic hydroxyl structure, can form strong non-covalent crosslinks with the amino or carboxyl groups of gelatin through hydrogen bonding and hydrophobic interactions. Furthermore, in the presence of metal ions, EGCG can also form dynamically reversible coordination bonds with metal ions, further enhancing the stability of the crosslinked network. Experiments showed that upon adding an aqueous solution of EGCG, the shell of the microgel immediately underwent a significant change, with the thickness of the gel shell changing from the micrometer scale (20-50 μm) to the nanometer scale (below 300 nm). This phenomenon has never been reported in the crosslinking process of gel blocks or solid microgels. The applicant speculates that the strong surface condensation reaction dominated by epigallocatechin gallate may first occur at the outer interface of the microgel shell. EGCG molecules tend to accumulate at the interface and react rapidly with the gelatin on the shell surface, forming an ultrathin but highly crosslinked dense film, while some unreacted loose network may still remain inside the shell. During the subsequent reaction, the cross-linking agent gradually diffuses from the outer surface inward, resulting in a gradient distribution of cross-linking density that decreases from the outside to the inside. The highly cross-linked regions on the outer surface form a rigid film, while the inner layer, due to its lower degree of cross-linking, may retain some swelling capacity, but the overall shell thickness is significantly reduced due to the densification of the outer layer. GA can undergo strong covalent interactions with gelatin chains, forming a rigid covalent network through Schiff base reactions. Therefore, a multi-responsive microgel with an ultrathin shell is formed. Attached Figure Description

[0018] Figure 1 The diagram shows the structure of the microfluidic device in Example 1 and the preparation process of the multi-response microgel with an ultrathin shell in Example 2.

[0019] Figure 2 This is a schematic diagram of the microgel formation principle in Example 1, where a represents the focusing glass capillary microfluidic device and the emulsion formation process, and b and c represent the emulsion microgel structure and its cooling gelation process.

[0020] Figure 3 The curves are first-order kinetic fitting curves of the swelling process of microgels with different SA contents in Example 1.

[0021] Figure 4 The equilibrium swelling ratio and the three-phase ratio of the gel layer, interstitial layer and inner oil phase of the microgels with different sodium alginate contents in Example 1 are shown.

[0022] Figure 5 The green fluorescent region represents the temperature-dependent permeability of the microgel in Example 1, and the relative encapsulation rate of the microgel for different molecular weights of FITCDextran under different temperature conditions represents the permeability of the microgel at different temperature conditions.

[0023] Figure 6 The images show the optical microstructures and fluorescence fields of different cross-linked microgels prepared in Example 2. The green area represents the green fluorescence of FITC-DEX with a molecular weight of 4000.

[0024] Figure 7 The release rate of different cross-linked microgels prepared in Example 2 under vortex shear force.

[0025] Figure 8 Temperature response release curves of various microgels prepared in Example 2.

[0026] Figure 9 The pH response release curves of various microgels prepared in Example 2 are shown.

[0027] Figure 10 The image shows the SEM microstructure of the various microgels prepared in Example 2. Detailed Implementation

[0028] To make the technical problems solved, the technical solutions, and the beneficial effects of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0029] Example 1 This embodiment provides a method for preparing a stable and uniform O / G / O type dual emulsion microgel, specifically by using a microfluidic device to prepare a stable and uniform O / G / O type dual emulsion microgel.

[0030] like Figure 1 The diagram shows the structure of the microfluidic device used in this embodiment. The microfluidic device includes a first raw material tube, a second raw material tube, and a third raw material tube. One end of the first, second, and third raw material tubes is connected, and an inner oil phase inlet is provided at the connection point for injecting the inner oil phase. The other end of the first, second, and third raw material tubes are outlets. Along the direction from the inner oil phase inlet to the outlet, each of the first, second, and third raw material tubes is sequentially provided with an intermediate aqueous phase inlet and an outer oil phase inlet for injecting the intermediate aqueous phase and the outer oil phase, respectively. A temperature heating device is also provided inside the microfluidic device to heat the interior of the microfluidic device and regulate the internal temperature of the chip. In this embodiment, the first, second, and third raw material tubes are all glass capillaries, and the inner diameter of each of the first, second, and third raw material tubes is 100 μm.

[0031] use Figure 1 The method for preparing a stable and uniform O / G / O type dual emulsion microgel using the microfluidic device shown includes: (1) Mix corn oil and 1 wt% polyglycerol ricinoleate (i.e., the amount of polyglycerol ricinoleate added is 1 wt% of corn oil) to prepare sufficient internal oil phase O1; (2) Mix corn oil with 3 wt% polyglycerol ricinoleate (i.e., the amount of polyglycerol ricinoleate added is 3 wt% of corn oil) to prepare sufficient external oil phase O2; (3) Mix 10wt% gelatin (i.e., the amount of gelatin added is 10wt% of water), 0% or 0.5wt% or 1.5wt% or 2.5wt% or 3.5wt% or 5wt% sodium alginate (i.e., the amount of sodium alginate added is 0wt%, 0.5wt%, 1.5wt%, 2.5wt%, 3.5wt%, 5wt% of water, respectively) with water to prepare six intermediate aqueous phases G respectively; (4) The inner oil phase O1, the outer oil phase O2, and the six intermediate aqueous phases G were centrifuged at 8000 rpm for 10 minutes and filtered with a 0.22 μm pore size nylon filter to remove large particles in the solution, so as to ensure the smoothness and stability of the flow into the microfluidic chip. (5) Use three syringe pumps to inject the above three-phase liquid into the atmosphere at 60°C. Figure 1 In the microfluidic device, the flow rates of the three-phase liquids are adjusted to ensure the generation of a uniform and stable dual emulsion. The flow rate of the inner oil phase O1 is 800 μL / h, the flow rate of the middle water phase G is 3200 μL / h, and the flow rate of the outer oil phase O2 is 8000 μL / h. The three-phase fluids form a focused microfluidic interface in the microfluidic device to generate a mononuclear dual emulsion. (6) In a microfluidic device, a mononuclear dual emulsion was introduced into a collection tube, which was then placed in an ice-water bath to promote rapid solidification of the aqueous phase. Subsequently, it was left to stand at 4°C for 8 hours to ensure that the droplets flocculated to the bottom of the centrifuge tube under gravity, avoiding eccentricity and breakage. Then, the upper outer oil phase was carefully removed with a syringe, leaving only the lower layer of O / G / O dual emulsion microgels that had solidified at low temperature, resulting in six O / G / O type dual emulsion microgels (named 0%SA@GEL, 0.5%SA@GEL, 1.5%SA@GEL, 2.5%SA@GEL, 3.5wt%SA@GEL and 5%SA@GEL, respectively).

[0032] A schematic diagram of the microfluidic device in this embodiment is shown below. Figure 2 As shown in a, a mononuclear O / G / O dual emulsion microgel system was successfully prepared by precisely controlling the flow rate of the three channels.

[0033] Test and Results Analysis The properties of the microgels prepared in Example 1 were determined using the following methods: I. Determination of the properties of the dual emulsion microgel prepared in step (6) The O / G / O dual emulsion microgels collected in an ice-water bath were placed in a vacuum filtration apparatus. Ethyl acetate was used as the detergent, and a 0.22 μm pore size nylon filter was used to slowly dry the residual outer oil phase. This process was repeated three times to ensure the integrity of the emulsion microgel structure and the absence of oil on the surface. The images of the microgels under a bright-field microscope were analyzed using ImageJ software to determine the initial overall droplet diameter (OD), inner oil droplet diameter (ID), and the volume fraction of inner oil droplets in the overall microgel (Ф) for each O / G / O microgel sample. The results are shown in Table 1.

[0034] Table 1 *Different lowercase letters in the labeling of samples in the same column indicate significant differences (P<0.05).

[0035] In summary, under optimized parameter conditions, the internal oil phase V in this embodiment is... O1 =800 μL / h, intermediate gel phase (10 wt% gelatin, 2.5 wt% SA), V G =3200 μL / h, external oil phase V O2 A homogeneous mononuclear dual emulsion with an outer diameter of 332±5.6μm and an inner droplet diameter of 273±6.2μm was obtained at 8000 μL / h and 60℃, and transformed into a microgel upon rapid cooling (see...). Figure 2 (b and c in the text). In addition, changing the amount of sodium alginate added to the intermediate gel phase (SA=0%, 0.5%, 1.5%, 2.5%, 3.5%, 5%) can flexibly control the structural size of the emulsion microgel and the ratio of the microgel shell-core structure.

[0036] II. Effects of different sodium alginate addition amounts on the swelling kinetics of O / G / O microgels The swelling process of the microgel exhibits a rapid initial rate, followed by a significant slowdown. This water absorption phenomenon is primarily due to the osmotic pressure of the hydrogel matrix. By measuring the swelling ratio of the microgel shell at different time points and fitting it with a first-order reaction kinetic model, the water absorption behavior was quantitatively described. The equations used are as follows: Qt=Qe(1-e -kt ) In this equation, only the water adsorption behavior of the gel layer is calculated. Qe (g / g) represents the mass of water adsorbed by the microgel shell when a single microgel system reaches equilibrium. Qt (g / g) represents the mass of water adsorbed by the microgel shell within a given time. t (min) represents time. k (g / g·min) represents the first-order water absorption rate constant. The kinetic parameters are determined using the Levenberg–Marquardt (L–M) algorithm.

[0037] The fitted curve is shown Figure 3 In the fitting results, the following are observed: (1) The effect of sodium alginate (SA) addition on the equilibrium water absorption of the microgel ( ) and water absorption rate constant ( It has a significant impact.

[0038] (2) The sample without sodium alginate had a lower equilibrium water absorption and showed a shrinkage trend after swelling.

[0039] (3) As the amount of sodium alginate added increases, The SA content increased significantly, and the swelling properties of the microgel were positively correlated.

[0040] III. Swelling Model of O / G / O Microgels with Different Sodium Alginate Additions (1) Fitting and establishing the microgel swelling model The Fick diffusion equation was used to study how solvent molecules enter and are absorbed into the microgel shell: .

[0041] This equation only calculates the water adsorption behavior of the gel layer. F represents the swelling ratio, which is the ratio of the amount of water absorbed at a certain moment to the equilibrium water absorption (dimensionless). W t W represents the mass (g) of water absorbed by the microgel shell at time t. e k represents the mass (g) of water absorbed when the microgel shell reaches equilibrium. D : Diffusion constant, representing the swelling rate of the microgel shell. t: Time (sec). n: Diffusion index, reflecting the diffusion mechanism. The diffusion index (n) and diffusion constant (k) of the microgel shell are calculated by fitting the water absorption data of the microgel over time to the equation. D ).

[0042] Diffusion index (n) and diffusion constant K of microgels with different sodium alginate contents D See Table 2.

[0043] Table 2 (2) Effect of sodium alginate content on the swelling rate of microgels: The equilibrium swelling ratio of microgels with different sodium alginate contents and the three-phase ratio of the gel layer, interstitial layer, and inner oil phase after swelling are shown in the figure. Figure 4 .

[0044] When the content is 0%, the microgel shell is composed of 10% pure gelatin, and its network relies on hydrogen bonds between the triple helix chains of gelatin to maintain its structure. Due to the weak mobility of gelatin chain segments (rigid triple helix is ​​dominant), the penetration height of solvent molecules in the gel network is limited, and the diffusion index n reaches its lowest value (0.0447). At this time, the hydrogen bond network inside the gel inhibits the permeation rate of water molecules compared with other experimental groups. The experiment observed that the water absorption mass is the lowest at swelling equilibrium, and it is difficult to form obvious gap spaces (GAP) during the swelling process of the shell.

[0045] As the SA content increases (0.5%~5%), gelatin and SA form a stable semi-interpenetrating network through hydrogen bonding and electrostatic interactions, significantly altering the shell swelling behavior. Figure 4 a) In this context: On the one hand, the flexible carboxylate groups (COO) of the SA molecular chain - Inserting gelatin into a triple helix network creates a more open porous structure. Swelling experiment data also shows that the diffusion index n reaches its peak (0.3189) when SA=2.5%, indicating a significant change in the way water molecules permeate. On the other hand, the difference in chain relaxation rates between gelatin (relaxation time τ1=120s) and SA (τ2=320s) leads to phased swelling. In the initial swelling stage, gelatin chains relax preferentially, allowing water molecules to rapidly permeate through the semi-interpenetrating network pores, resulting in a sharp increase in gel surface area. In the middle and later stages of swelling, the slow relaxation of SA chains triggers overall network rearrangement, leading to a dynamic evolution in the gel layer thickness—first thickening and then thinning—ultimately reaching swelling equilibrium. This dynamic pore reconstruction process increases the equilibrium swelling rate of the SA=5% microgel by approximately 5 times compared to a pure gelatin shell.

[0046] (3) Effect of sodium alginate content on the structure ratio of microgel GAP layer: Table 3 shows the water adsorption capacity, gel layer ratio, and interstitial layer ratio of microgels with different sodium alginate contents.

[0047] Table 3 The six microgel samples with different SA contents studied in this embodiment all produced a certain gap space after swelling. This gap space can be used for drug delivery, microresponse device, and microsensor design, so selecting a larger gap space is of great significance for subsequent experimental design. The SA content and the ratio of gap space are positively correlated non-linearly. Figure 4(b) In this study, the microgel with SA=2.5% exhibited the largest interstitial space and the highest relative n value after swelling, while the addition of higher SA content did not result in a larger interstitial space. This phenomenon suggests that the regulation of microgel structure by SA content may have a threshold effect (SA=2.5%). Exceeding this threshold, excessive SA molecules may exceed the capacity of the gelatin network, forming locally SA-rich regions. During swelling, the difference in swelling rate leads to interfacial stress concentration, resulting in microcracks or pore collapse. Furthermore, excessive SA may interfere with the triple helix crosslinking of gelatin, reducing the mechanical strength of the network. In the later stages of swelling, the negative impact on hydration stress offsets the positive effect of pore optimization, ultimately leading to a decrease in the proportion of GAP structure. Therefore, at SA=2.5%, the moderate network porosity and dynamic relaxation characteristics allow the microgel to possess both a high swelling rate and the largest interstitial space while avoiding microphase separation and shell structure instability. Considering all performance aspects, it is most suitable for further processing and modification.

[0048] IV. Effects of Temperature on the Permeability and Hydrodynamic Pore Size of Microgel Molecules To investigate the effect of temperature on the permeability of microgels and estimate their hydrodynamic pore size, permeation experiments were conducted using fluorescently labeled dextran (FITC-Dextran, molecular weight range: 4,000-150,000 g / mol). The washed emulsion microgels were placed on custom-made concave slides, and solutions of FITC-Dextran with different molecular weights were added. The microgels were incubated at 0℃, 10℃, 20℃, and 30℃ for 30 minutes each. Fluorescence images of the microgels were dynamically acquired using an inverted fluorescence microscope (FITC excitation wavelength 470–495 nm, emission wavelength 510–550 nm, 40× objective lens), with sampling intervals of 30 minutes for 24 hours. The regions of interest (ROIs) and background of the microgels were delineated using LASX software, and the internal fluorescence intensity was qualitatively analyzed.

[0049] The results are as follows Figure 5 As shown, the results indicate that: (1) For FITC-DEX-4000 (hydrodynamic diameter) Within the range of 0–30℃, the fluorescence intensity inside and outside the microgel is basically the same, indicating that the pore size of the microgel shell is greater than 2.8 nm at all test temperatures. (2) For FITC-DEX-10000 ( Within the range of 0–30℃, high fluorescence intensity can still be observed inside the microgel, but the uniformity of distribution is lower than that of the 4000Da group, indicating that some molecules may interact with the gel network. (3) For FITC-DEX-40000, the fluorescence intensity inside the microgel is significantly lower than that outside at 0℃ and 10℃, indicating that the gel network shrinks at this time and the effective pore size is less than 4.6nm; (4) For FITC-DEX-150000, the fluorescence intensity inside the microgel was significantly lower than that outside at all temperatures, and the fluorescence intensity outside the edge of the microgel was enhanced at 20℃ and 30℃, which proved that the increase in pore size led to the blockage and enrichment of macromolecules on the periphery of the gel, reflecting the selective enrichment effect of the microgel network on substances in the solution.

[0050] In summary, the O1 / G / O2 dual emulsion droplets prepared in this embodiment exhibit high monodispersity (PDI < 0.1). The droplet size structure can be controllably adjusted from 150 to 430 μm by regulating the SA content (0%-5%). After cooling, the dual emulsion system forms an O1 / Gel / O2 dual emulsion microgel. The sodium alginate (SA) content significantly affects the swelling behavior of the microgel in water; its equilibrium swelling rate is positively correlated with the SA content, and the swelling process exhibits Non-Fickian anomalous diffusion characteristics (n < 0.5). During the microgel swelling process, an aqueous gap can spontaneously form between the O1 and Gel phases, forming an O1 / Gap / Gel structure. When the SA content reaches 2.5% Wt, the volume ratio of the aqueous gap structure after microgel swelling can reach 54%. The O1 / Gap / Gel dual emulsion microgel has a network pore size that varies with temperature; the hydrodynamic pore size of the microgel is less than 4.6 nm at 0-10℃, while the pore size reaches its maximum at 30℃.

[0051] Example 2 Based on the structure of the O / G / O type dual emulsion microgel prepared in Example 1, this invention systematically constructs a multi-layered environmentally responsive microgel system containing single networks (SN), dual networks (DN), and triple networks (TN) by designing multiple sequential crosslinking strategies for EGCG, zinc sulfate (ZnSO4), and glutaraldehyde (GA). This provides a method for preparing multi-layered responsive microgels with ultrathin shells. The preparation process is as follows: Figure 1 As shown, the specific method is as follows: The dual emulsion microgel prepared in Example 1 was washed, dispersed, and swollen to volume stability at room temperature using 2.5% SA@GEL. Subsequently, the fully swollen microgel was subjected to surface and interfacial crosslinking according to nine crosslinking sequences: ZnSO4, ZnSO4-EGCG, ZnSO4-EGCG-GA, EGCG, EGCG-GA, EGCG-GA-ZnSO4, GA, GA-EGCG, and GA-EGCG-ZnSO4.

[0052] Specifically, the method for preparing a multi-responsive microgel with an ultrathin shell using the dual emulsion microgel 2.5%SA@GEL prepared in Example 1 includes: I. Preparation method of dual-network EGCG-GA@GEL: 1. Add 20 ml of the dual emulsion microgel 2.5% SA@GEL prepared in Example 1 to... Figure 1 In the reaction vessel shown, the target aqueous solution is washed with ethyl acetate and then dispersed in the target aqueous solution. The target aqueous solution may contain, but is not limited to, macromolecular proteins, nanoparticles, small molecule active peptides, drug molecules, etc., and is soaked for 20 minutes. In this embodiment, the target aqueous solution is a macromolecular protein aqueous solution that is soaked for 20 minutes until it swells to a stable volume.

[0053] 2. Add 100 ml of crosslinking agent 1 (5 mg / ml epigallocatechin gallate (EGCG) aqueous solution) to the dispersion system, ensuring that the particles are fully immersed in the excess crosslinking agent, and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 3 (2.5% glutaraldehyde (GA) aqueous solution) to the dispersion system, and crosslink for 3 min. After crosslinking, rinse with pure water to obtain EGCG-GA@GEL.

[0054] II. Preparation method of dual-network GA-EGCG@GEL: 1. The processing procedure is the same as EGCG-GA@GEL.

[0055] 2. Add 100 ml of crosslinking agent 3 (2.5% glutaraldehyde (GA) aqueous solution) to the dispersion system, ensuring that the particles are fully immersed in the excess crosslinking agent, and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 1 (5 mg / ml epigallocatechin gallate (EGCG) aqueous solution) to the aqueous dispersion system, and crosslink for 3 min. After crosslinking, rinse with pure water to obtain GA-EGCG@GEL.

[0056] III. Preparation Method of Dual Network – ZN-EGCG@GEL 1. The processing procedure is the same as EGCG-GA@GEL.

[0057] 2. Add 100 ml of crosslinking agent 2 (1% zinc sulfate (ZnSO4) aqueous solution) to the dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 1 (5 mg / ml epigallocatechin gallate (EGCG) aqueous solution) to the dispersion system to ensure that the particles are fully immersed in the excess crosslinking agent and crosslink for 3 min. After crosslinking, rinse with pure water to obtain ZN-EGCG@GEL.

[0058] IV. Preparation method of triple network - EGCG-GA-ZN@GEL: 1. The processing procedure is the same as EGCG-GA@GEL.

[0059] 2. Add 100 ml of crosslinking agent 1 (5 mg / ml epigallocatechin gallate (EGCG) aqueous solution) to the dispersion system, ensuring that the particles are fully immersed in the excess crosslinking agent, and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 3 (2.5% glutaraldehyde (GA) aqueous solution) to the dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 2 (1% zinc sulfate (ZnSO4) aqueous solution) to the dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water to obtain EGCG-GA-ZN@GEL.

[0060] V. Preparation method of triple network - GA-EGCG-ZN@GEL: 1. The processing procedure is the same as EGCG-GA@GEL.

[0061] 2. Add 100 ml of crosslinking agent 3 (2.5% glutaraldehyde (GA) aqueous solution) to the dispersion system, ensuring that the particles are fully immersed in the excess crosslinking agent, and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 1 (5 mg / ml epigallocatechin gallate (EGCG) aqueous solution) to the aqueous dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 2 (1% zinc sulfate (ZnSO4) aqueous solution) to the aqueous dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water to obtain GA-EGCG-ZN@GEL.

[0062] VI. Preparation method of triple network - ZN-EGCG-GA@GEL: 1. The processing procedure is the same as EGCG-GA@GEL.

[0063] 2. Add 100 ml of crosslinking agent 2 (1% zinc sulfate (ZnSO4) aqueous solution) to the dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 1 (5 mg / ml epigallocatechin gallate (EGCG) aqueous solution) to the dispersion system to ensure that the particles are fully immersed in the excess crosslinking agent and crosslink for 3 min. After crosslinking, rinse with pure water. Add 100 ml of crosslinking agent 3 (2.5% glutaraldehyde (GA) aqueous solution) to the dispersion system and crosslink for 3 min. After crosslinking, rinse with pure water to obtain ZN-EGCG-GA@GEL.

[0064] VII. Preparation method of single-layer network - ZN@GEL 1. The processing procedure is the same as EGCG-GA@GEL.

[0065] 2. Add 100 ml of crosslinking agent (an aqueous solution of zinc sulfate (ZnSO4) with a mass concentration of 1%) to the dispersion system, ensuring that the microparticles are fully immersed in the excessive crosslinking agent, and crosslink for 3 min; after crosslinking, rinse with pure water to obtain ZN@GEL.

[0066] VIII. Single Network - Preparation Method of EGCG@GEL 1. The treatment process is the same as that of EGCG-GA@GEL.

[0067] 2. Add 100 ml of crosslinking agent (an aqueous solution of epigallocatechin gallate (EGCG) with a concentration of 5 mg / ml) to the dispersion system, ensuring that the microparticles are fully immersed in the excessive crosslinking agent, and crosslink for 3 min; after crosslinking, rinse with pure water to obtain EGCG@GEL.

[0068] IX. Single Network - Preparation Method of GA@GEL 1. The treatment process is the same as that of EGCG-GA@GEL.

[0069] 2. Add 100 ml of crosslinking agent (an aqueous solution of glutaraldehyde (GA) with a mass concentration of 2.5%) to the dispersion system, ensuring that the microparticles are fully immersed in the excessive crosslinking agent, and crosslink for 3 min; after crosslinking, rinse with pure water to obtain GA@GEL.

[0070] Testing and Result Analysis The properties of the 9 microgels prepared in Example 2 were measured, and the measurement method is as follows: I. Analysis of Structural Changes in the Process of Constructing Multiple Responsive Microgels The optical microscopic structures and fluorescence field images of different crosslinked microgels are as Figure 6 shown, where the green area is the green fluorescence of FITCDEX with a molecular weight of 4000, as Figure 6 shown. Among the three single crosslinked microgels, the crosslinking density of ZN@GEL < GA@GEL < EG@GEL, but the temperature stability of the microgels treated with the three crosslinking agents at physiological temperature is relatively low, which limits their further application. Even for EG@GEL with the highest crosslinking density, the structure will collapse and break within 5 minutes at physiological temperature.

[0071] Based on the above experimental findings and cutting-edge theoretical support, the applicant conducted secondary and tertiary cross-linking of three microgels, ZN@GEL, GA@GEL, and EG@GEL, on the basis of primary cross-linking to regulate their stability and release capacity at physiological temperatures. This resulted in six secondary cross-linked microgels: ZN-EG@GEL, ZN-GA@GEL, GA-EG@GEL, GA-ZN@GEL, EG-GA@GEL, and EG-ZN@GEL, and six tertiary cross-linked microgels: ZN-EG-GA@GEL, ZN-GA-ZN@GEL, GA-EG-ZN@GEL, GA-ZN-EG@GEL, EG-GA-ZN@GEL, and EG-ZN-GA@GEL. However, preliminary experiments evaluating their temperature stability revealed that the structures and temperature stability of the three microgels, ZN-GA@GEL, GA-ZN@GEL, and EG-ZN@GEL, did not change significantly. Therefore, subsequent experiments and discussions mainly focused on six microgels with relatively stable structures and different release properties: ZN-EG@GEL, GA-EG@GEL, EGGA@GEL, ZN-EG-GA@GEL, GA-EG-ZN@GEL, and EGGA-ZN@GEL.

[0072] like Figure 6 As shown, under bright-field fluorescence microscopy, six microgels—ZN-EG@GEL, GA-EG@GEL, EG-GA@GEL, ZN-EGGA@GEL, GA-EGZN@GEL, and EGGA-ZN@GEL—all exhibited uniform and dense film layers, with minimal release of contents under room-temperature fluorescence conditions. Furthermore, nano-aggregates induced by ZN ions were observed within the film structures of ZN-EG-GA@GEL, GA-EG-ZN@GEL, and EGGAZN@GEL microgels. This is because during the swelling process of the gel network, some short gelatin chains diffused into the interstitial regions. During cross-linking, a small amount of ions and polyphenols formed nanoparticles, which further aggregated and adsorbed at the microgel interface. These nano-aggregates are essentially similar in composition to the shell layer. In subsequent experiments, these nano-aggregates decomposed and disappeared as reversible chemical bonds in the film structure broke.

[0073] II. Evaluation of the mechanical and chemical stability of multi-responsive microgels To evaluate the mechanical stability of the microgels, the rupture of microgels with equal amounts of embedded fluorescent probes under shear force was tested. Control@GEL was a microgel that only underwent swelling and adsorption without surface cross-linking.

[0074] The results are as follows Figure 7As shown, experimental results demonstrate that microgels containing covalently cross-linked composite networks exhibit significantly higher structural stability compared to ZN-EGCG microgels with single-network cross-linking or only MPN network cross-linking, maintaining most of their structural integrity even under maximum shear stress. The synergistic effect of the covalently cross-linked network and the MPN network endows the microgels with both high strength and high toughness. In the multi-responsive microgels constructed with composite cross-linking, the covalently cross-linked network bears the main load, while the MPN network dissipates energy through a dynamic and reversible fracture-reorganization process, thereby greatly enhancing the mechanical stability of the microgels.

[0075] III. Measurement of the temperature-responsive release properties of microgels To investigate the temperature-responsive release behavior of the microgels, the experiment combined real-time microscopic observation with batch release analysis: First, single microgels were prepared in situ on a single concave slide adapted for a fluorescence inverted microscope. These microgels were placed on a temperature-controlled stage with an accuracy of ±0.1℃. Fluorescence images of the microgels were dynamically acquired using a fluorescence inverted microscope (FITC excitation wavelength 470–495 nm, emission wavelength 510–550 nm, 40× objective lens) at 30-minute intervals, with continuous monitoring for 24 hours. The region of origin (ROI) of the microgels and the background region were delineated using LASX software, and the rate of decrease in net fluorescence intensity was calculated to characterize the release kinetics of FITC-DEX.

[0076] Simultaneously, microgel particles loaded with FITC-DEX were prepared in batches according to Example 2. These particles were dispersed in PBS at pH 7 and placed in dialysis bags with a molecular weight cutoff of 10 kDa. Release experiments were conducted in a constant-temperature shaker (37°C, 150 rpm). Samples were taken at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. After centrifugation, the supernatant was collected, and the fluorescence intensity was measured using a fluorescence spectrophotometer (excitation wavelength 494 nm, emission wavelength 518 nm, slit width 5 nm). The cumulative release was calculated using the FITC-DEX standard curve (concentration range 0.1–50 μg / mL, R² > 0.99).

[0077] All operations were conducted under light-protected conditions, with each experiment repeated three times. The accuracy and reliability of the temperature-responsive release mechanism were verified by comparing the consistency of single-particle and population release data.

[0078] The results are as follows Figure 8 As shown, the following conclusions can be drawn: (1) Under pH 7 conditions, the order of time required for complete release of model molecules is: ZN-EG-GA@GEL>EG-GA-ZN@GEL>EG-GA@GEL>GA-EG-ZN@GEL>GA-EG@GEL>GA-EG-ZN@GEL>GA-EG@GEL.

[0079] (2) The release time of the two types of double cross-linked microgels, EG-GA@GEL and GA-EG@GEL, is significantly shorter than that of the triple cross-linked system. At physiological temperature, the fluorescence intensity inside the microgel drops to the lowest level within 6 hours.

[0080] (3) The release rate of EG-GA@GEL in the first 3 hours was significantly lower than that of GA-EG@GEL, indicating that the cross-linking sequence has an important influence on the release behavior.

[0081] (4) The complete release time of EG-GA-ZN@GEL and GA-EG-ZN@GEL at physiological temperature is extended to 24 hours, indicating that the metal-phenol network (MPN) formed by zinc ions has better temperature stability.

[0082] (5) Among all samples, ZN-EG-GA@GEL exhibited the longest sustained-release time at physiological temperature, up to 50 hours.

[0083] IV. Determination of pH-responsive release performance of microgels To evaluate the pH-responsive release characteristics of the microgels, the experiment also employed a combination of real-time microscopic observation and batch release analysis: First, according to Example 2, single microgels were prepared in situ on a single concave slide for a fluorescence inverted microscope. These microgels were placed on a temperature-controlled stage with an accuracy of ±0.1°C. Fluorescence images of the microgels were dynamically captured using a fluorescence inverted microscope (RITC excitation wavelength 520–580 nm, emission wavelength 610–630 nm, 40× objective lens) every 10 minutes for 24 hours. The microgel region of interest (ROI) and background were defined using LASX software, and the net fluorescence intensity decrease rate was calculated to reflect the release dynamics of RITC-DEX.

[0084] Simultaneously, according to Example 2, microgel particles loaded with RITC-DEX were prepared in batches, dispersed in PBS at pH 5.4, and placed in dialysis bags with a molecular weight cutoff of 10 kDa. Release experiments were conducted in a constant-temperature shaker (37°C, 150 rpm). Samples were taken every 10 minutes, centrifuged, and the supernatant was collected. The fluorescence intensity was measured using a fluorescence spectrophotometer, and the cumulative release was calculated based on the RITC-DEX standard curve (concentration range 0.1–50 μg / mL, R² > 0.99).

[0085] The experiment was conducted entirely in the dark, with each group repeated three times. The accuracy and reliability of the pH response mechanism analysis were ensured by comparing the consistency of single-particle and group release data.

[0086] The results are as follows Figure 9 As shown, the following conclusions can be drawn: (1) At physiological temperature, compared with pH 7, all five microgels (EG-GA-ZN@GEL, ZN-EG-GA@GEL, EG-GA@GEL, GA-EG-ZN@GEL, GA-EG@GEL) showed high sensitivity to pH changes, exhibiting rapid release characteristics with sensitive pH response. The complete release time of the microgel-encapsulated cargo was significantly shortened from 6–50 hours under pH 7 conditions to 100–150 minutes.

[0087] (2) Among them, GA-EG-ZN@GEL showed the fastest release response, and the other groups, in order of response speed, were: GA-EG@GEL, EG-GA-ZN@GEL, EG-GA@GEL, and ZN-EG-GA@GEL. This order indicates that the participation of zinc ions helps to improve the pH response sensitivity of the microgels.

[0088] V. SEM microstructure of multi-responsive microgels The morphology and surface of six groups of responsive microgels, namely GA@GEL, GA-EG@GEL, EG-GA-ZN@GEL, EG-GA@GEL, ZN-EG-GA@GEL, and GA-EG-ZN@GEL, were observed by SEM.

[0089] The results are as follows Figure 10 As shown, the three groups of responsive microgels (GA@GEL, GA-EG@GEL, and EG-GA@GEL) without zinc ion involvement all formed dense film structures on their surfaces. No large network pores were observed after gel freeze-drying, consistent with our observations of gel interfacial polymerization under an optical microscope. This indicates that the shell structure of the microgels is not a visual effect caused by the difference in refractive indices between the gel and aqueous phases. Furthermore, no nano-aggregates were found on the microgel film surface, consistent with our observations under an optical microscope. However, varying degrees of nano-aggregate adhesion were observed on the surfaces of the EG-GA-ZN@GEL, ZN-EG-GA@GEL, and GA-EG-ZN@GEL microgels. ZN-EG-GA@GEL had the most particulate aggregates, followed by EG-GA-ZN@GEL; GA-EG-ZN@GEL had the fewest. We hypothesize that the MPN nano-aggregates enriched on the microgel surface are formed by the permeation of different amounts of polyphenols and zinc ions from the microgel shell due to gel network contraction during the cross-linking process. Furthermore, it plays a buffering role in the temperature response process, that is, the MPN particles on the surface decompose and diffuse first, and the MPN network inside decomposes and diffuses later.

[0090] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing a multi-responsive microgel with an ultrathin shell, characterized in that, Includes the following steps: S1. Prepare the internal oil phase, intermediate aqueous phase, and external oil phase; S2. The inner oil phase, the intermediate aqueous phase and the outer oil phase are respectively injected into a microfluidic device to prepare an O / G / O type dual emulsion microgel. S3. The O / G / O type dual emulsion microgel is subjected to a crosslinking reaction with a solution containing a crosslinking agent to obtain a multi-response microgel with an ultrathin shell.

2. The preparation method according to claim 1, characterized in that, In S1, the inner oil phase includes corn oil and polyglycerol ricinoleate, the intermediate aqueous phase includes gelatin, sodium alginate and water, and the outer oil phase includes corn oil and polyglycerol ricinoleate. The volume ratio of the inner oil phase, intermediate aqueous phase and outer oil phase is 1:3~5:9~11.

3. The preparation method according to claim 2, characterized in that, In S1, the amount of polyglycerol ricinoleate added in the inner oil phase is 0.5~1.5 wt% of corn oil; the amount of gelatin added in the intermediate aqueous phase is 9~11 wt% of water; the amount of sodium alginate added is 0.5~5 wt% of water; and the amount of polyglycerol ricinoleate added in the outer oil phase is 2.5~3.5 wt% of corn oil.

4. The preparation method according to claim 1, characterized in that, In S2, the microfluidic device includes a first raw material tube, a second raw material tube, and a third raw material tube. The first raw material tube is connected to one end of the second and third raw material tubes, and an inner oil phase inlet is provided at the connection point. The other end of the first, second, and third raw material tubes each has an outlet. Along the direction from the inner oil phase inlet to the outlet, the first, second, and third raw material tubes are each provided with an intermediate aqueous phase inlet and an outer oil phase inlet in sequence.

5. The preparation method according to claim 1, characterized in that, In S2, the inner oil phase, the intermediate aqueous phase, and the outer oil phase are injected into the microfluidic device at 55~65°C. The flow rate of the inner oil phase injected into the microfluidic device is 600~1000 μL / h, the flow rate of the intermediate aqueous phase injected into the microfluidic device is 2700~3700 μL / h, and the flow rate of the outer oil phase injected into the microfluidic device is 7500~8500 μL / h.

6. The preparation method according to claim 1, characterized in that, In S3, the crosslinking agent in the solution containing the crosslinking agent is at least one of zinc sulfate, epigallocatechin gallate, and glutaraldehyde, and the volume ratio of the O / G / O type dual emulsion microgel to the solution containing the crosslinking agent is 1:4~6.

7. The preparation method according to claim 6, characterized in that, The concentration of the solution containing zinc sulfate is 0.5-1.5%, the concentration of the solution containing epigallocatechin gallate is 4-6 mg / ml, and the concentration of the solution containing glutaraldehyde is 2-3%.

8. The preparation method according to claim 6, characterized in that, S3 includes the following steps: The O / G / O type dual emulsion microgel was washed and then dispersed in a solution containing the target embedding material and soaked for 10-30 min until it swelled to a stable volume to obtain a dispersion system; wherein, the solution containing the target embedding material contains macromolecular proteins and / or nanoparticles and / or small molecule active peptides and / or small drug molecules. Then crosslinking is performed according to one of steps (1)-(3): (1) The dispersion system is added to crosslinking agent 1 and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a multi-response microgel with an ultrathin shell. (2) Add the dispersion system to crosslinking agent 1, crosslink fully, and rinse with pure water after crosslinking to obtain an aqueous dispersion system; add crosslinking agent 2 to the aqueous dispersion system, crosslink fully, and rinse with pure water after crosslinking to obtain a multi-response microgel with an ultrathin shell; (3) The dispersion system is added to crosslinking agent 1 and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a first aqueous dispersion system. Crosslinking agent 2 is added to the first aqueous dispersion system and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a second aqueous dispersion system. Crosslinking agent 3 is added to the second aqueous dispersion system and fully crosslinked. After crosslinking, it is rinsed with pure water to obtain a multi-response microgel with an ultrathin shell. Wherein, crosslinking agent 1, crosslinking agent 2 and crosslinking agent 3 are respectively one of zinc sulfate, epigallocatechin gallate, and glutaraldehyde.

9. A multi-responsive microgel with an ultrathin shell, characterized in that, It is obtained by the preparation method described in any one of claims 1 to 8.

10. The multi-responsive microgel with an ultrathin shell according to claim 9, characterized in that, The multi-response microgel with an ultrathin shell comprises an inner core and a shell, the thickness of which is less than 300 nm.

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