Use of visible light-activated upconversion thermosensitive hydrogel in preparation of drugs for treating psoriasis

Abstract

The application discloses an application of visible light activated upconversion temperature-sensitive hydrogel in preparation of a medicine for treating psoriasis, and belongs to the technical field of biological medicines. 3+ The visible light activated upconversion temperature-sensitive hydrogel is prepared by preparing Ag@Pr 3+ :Y2SiO5 upconversion material, and dispersing the upconversion material in a temperature-sensitive hydrogel precursor solution composed of quaternized chitosan, beta-glycerophosphate and hydroxyethyl cellulose, and uniformly mixing to obtain the hydrogel. The hydrogel can convert 450nm visible light into 297-319nm ultraviolet light under visible light excitation, and can be converted from a sol state into a gel state at 32-37 DEG C. Animal experiments show that the hydrogel can significantly improve psoriasis-like skin lesions, inhibit an IL-23 / IL-17 inflammatory pathway and down-regulate a cell cycle and a DNA replication related pathway. The application provides a new strategy for precise and convenient treatment of psoriasis.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically the application of a visible light-activated upconversion thermosensitive hydrogel in the preparation of drugs for treating psoriasis. Background Technology

[0002] Psoriasis is a common immune-mediated skin disease characterized by skin inflammation, abnormal epidermal proliferation, and angiogenesis. In addition to visible erythematous plaques and scaly patches, psoriasis is often accompanied by itching, disfigurement, anxiety, depression, psoriatic arthritis, and cardiovascular and metabolic comorbidities, imposing a heavy physiological, psychological, and socioeconomic burden on patients. Many patients experience a chronic relapsing course throughout their lives, alternating between remission and exacerbations. Although biologics and small-molecule inhibitors have significantly improved the treatment of moderate to severe psoriasis, their long-term use may still be limited by factors such as treatment costs, accessibility, infection risk, systemic exposure, and individual variability in efficacy. Therefore, developing safe, topical, convenient treatment strategies suitable for long-term disease management remains of significant clinical importance, especially for patients with localized lesions or those requiring maintenance therapy.

[0003] Ultraviolet (UV) phototherapy, especially narrowband ultraviolet B (NB-UVB) phototherapy, remains one of the most important non-invasive, non-pharmacological treatments for psoriasis. Phototherapy can directly target the affected skin with minimal systemic drug exposure, making it valuable for patients unsuitable for systemic treatment, including some children, pregnant women, elderly patients, and those with infection-related concerns. NB-UVB (wavelength 311-313 nm) exerts its therapeutic effect by inducing apoptosis of excessively proliferating keratinocytes and pathogenic T cells, regulating antigen-presenting cells, and inhibiting pro-inflammatory cytokine networks. However, the clinical application of phototherapy is significantly limited by inconvenience and lack of precision. First, traditional phototherapy typically requires patients to visit hospitals or clinics multiple times a week for weeks to months, which is time-consuming and inconvenient, leading to poor treatment accessibility and low patient compliance. Second, traditional UV light delivery often uses large-area irradiation or fixed-shape phototherapy equipment, making it difficult to precisely target irregularly shaped lesions and specific anatomical locations. Unnecessary exposure of surrounding healthy skin can lead to erythema, burning, photodamage, and safety concerns related to cumulative UV exposure. Therefore, there is an urgent need to develop a local phototherapy strategy that can improve lesion coverage while minimizing UV exposure to non-target areas.

[0004] Upconversion nanoparticles (UCNPs) offer a novel approach to addressing the aforementioned challenges by separating the external excitation source from the therapeutic ultraviolet output. UCNPs can sequentially absorb two or more low-energy, long-wavelength photons and emit higher-energy, shorter-wavelength photons, including ultraviolet light. This optical property allows for the use of relatively safe and readily available visible light as an external excitation source to activate light-converting materials placed directly on the surface of psoriatic lesions. However, to achieve effective application of UCNPs in dermatology, a suitable local delivery carrier is needed to ensure uniform dispersion and stable retention of the particles on the affected skin, adapting to uneven lesion morphology and forming a stable therapeutic interface.

[0005] In view of the shortcomings of the existing technologies, there is an urgent need to develop a new local phototherapy strategy for psoriasis that can generate therapeutic ultraviolet light using a convenient and safe visible light source, achieve adhesive coverage of irregular skin lesions and stable retention of light conversion materials through a suitable local delivery carrier, avoid interference with light transmission by the carrier, and be easy to remove after treatment. Summary of the Invention

[0006] Therefore, the purpose of this invention is to provide the application of a visible light-activated upconversion thermosensitive hydrogel in the preparation of a drug for treating psoriasis. This hydrogel can significantly improve psoriasis-like skin lesions, inhibit the IL-23 / IL-17 inflammatory pathway and downregulate cell cycle and DNA replication-related pathways, and has good biocompatibility.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides the application of a visible light-activated upconversion thermosensitive hydrogel in the preparation of a drug for treating psoriasis. The visible light-activated upconversion thermosensitive hydrogel is prepared by the following method: (1) Preparation of Pr 3+ Y2SiO5 nanoparticles, for the Pr 3+ Y2SiO5 nanoparticles were modified with amino groups. (2) The amino-modified Pr 3+ Y₂SiO₅ nanoparticles were dispersed in water and heated to 90-110℃. An aqueous solution of silver nitrate and KH-550 was added, and the mixture was stirred. Then, trisodium citrate solution was added dropwise. The precipitate was collected, washed, and dried to obtain Ag@Pr 3+ Y2SiO5 upconversion material; (3) Quaternized chitosan, β-glycerol phosphate and hydroxyethyl cellulose were mixed under ice bath conditions to obtain a thermosensitive hydrogel precursor solution; the Ag@Pr obtained in step (2) was then mixed with the quaternized chitosan, β-glycerol phosphate and hydroxyethyl cellulose to obtain a thermosensitive hydrogel precursor solution. 3+Y2SiO5 upconversion material is dispersed in the thermosensitive hydrogel precursor solution and mixed evenly to obtain the visible light activated upconversion thermosensitive hydrogel.

[0008] Preferably, in step (1), Pr 3+ The molar doping amount in Y2SiO5 is 1%-5%.

[0009] Preferably, in step (2), the Pr 3+ The molar ratio of Y2SiO5, silver nitrate and trisodium citrate is 0.02:(0.0009-0.0036):(0.0001-0.0026).

[0010] Preferably, the mass ratio of the quaternized chitosan, β-glycerol phosphate, and hydroxyethyl cellulose is (0.5-2):2:1.

[0011] Preferably, the Ag@Pr 3+ Y2SiO5 upconversion material emits ultraviolet light with wavelengths of 297-319nm when excited by 450nm visible light.

[0012] More preferably, the irradiation time of the visible light is 15-45 minutes.

[0013] Preferably, the upconversion thermosensitive hydrogel transforms from a sol state to a gel state at a temperature of 32-37°C.

[0014] Preferably, the drug treats psoriasis by inhibiting the IL-23 / IL-17 inflammatory pathway.

[0015] Preferably, the drug treats psoriasis by downregulating cell cycle and DNA replication-related pathways.

[0016] Preferably, the upconversion quantum yield of the visible light activated upconversion thermosensitive hydrogel under visible light irradiation is ≥10%.

[0017] Compared with the prior art, the present invention has the following advantages: (1) Ag@Pr prepared in this invention 3+Y₂SiO₅ upconversion material emits ultraviolet light with wavelengths of 297-319 nm under 450 nm visible light excitation. This emission wavelength highly matches the treatment window (311-313 nm) of narrow-spectrum medium-wave ultraviolet B (NB-UVB) phototherapy for psoriasis. Through Ag surface modification, the upconversion quantum yield increased from 3.95% to 10.92%, an improvement of approximately 2.8 times, significantly enhancing the visible-to-ultraviolet conversion efficiency and ensuring the required ultraviolet light intensity for treatment. Simultaneously, this hydrogel can transform from a sol state to a gel state within approximately 5 minutes at a body temperature range of 32-37℃ and can be peeled off completely from the skin surface after treatment, exhibiting good temperature responsiveness and ease of use.

[0018] (2) The hydrogel matrix of this invention is composed of quaternized chitosan, β-glycerophosphate, and hydroxyethyl cellulose, without the addition of pyrrole and dopamine hydrochloride. This avoids the light-shielding effect of the dark polymer products of polydopamine on visible light, ensuring sufficient penetration of excitation light and upconversion ultraviolet emission efficiency. This hydrogel has good tissue adhesion and deformability, enabling it to closely adhere to irregularly shaped psoriatic lesions, achieving spatial confinement of ultraviolet light generation and reducing unnecessary irradiation of surrounding healthy skin. In vitro CCK-8 experiments show that in Ag@Pr 3+ When the concentration of Y2SiO5 does not exceed 500 μg / mL, the survival rates of HaCaT, DC2.4 and T cells are maintained above 85%, showing good biocompatibility. However, after activation by visible light, the viability of HaCaT cells is significantly reduced to about 60%, and the survival rates of DC2.4 and T cells are reduced to about 50% and 40%, respectively, achieving the phototoxic effect of on-demand activation.

[0019] (3) In an IMQ-induced psoriasis-like mouse model, hydrogel plus phototherapy significantly improved erythema, scaling, and skin thickening, with a significantly lower total PASI score compared to the IMQ model group, showing efficacy comparable to calcipotriol. Histological analysis showed that this treatment significantly reduced epidermal thickness, decreased Ki67-positive proliferating cells, and inhibited NF-κB activation and CD45-positive inflammatory cell infiltration. qRT-PCR results showed that the mRNA expression levels of pro-inflammatory cytokines Tnf-α, Il-1β, Il-17f, and chemokine Cxcl10 were significantly downregulated. Splenomegaly was reduced, and serum IL-17A and IL-23 levels were significantly decreased, indicating that this treatment can inhibit psoriasis-related inflammatory responses at both local and systemic levels.

[0020] (4) Flow cytometry and RNA sequencing further revealed its mechanism of action; hydrogel + phototherapy can increase CD11c in skin lesions. + Dendritic cells decreased from 19.0% to 7.77%, CD11b + Ly6G +Neutrophils decreased from 51.1% to 26.4%, and CD45 levels were significantly reduced. + CD3 + T cell infiltration. Transcriptome analysis showed significant negative enrichment in the cell cycle pathway (NES=-2.58) and DNA replication pathway (NES=-2.49), and positive enrichment in the PPAR signaling pathway (NES=1.74). These results indicate that this hydrogel exerts its anti-psoriatic effect through multiple mechanisms, including inhibiting the IL-23 / IL-17 inflammatory axis, downregulating cell cycle and DNA replication-related pathways, and promoting skin barrier repair, providing a novel technical solution for precise, convenient, and localized phototherapy of psoriasis. Attached Figure Description

[0021] Figure 1 For Ag@Pr 3+ Preparation and characterization results of Y2SiO5 upconversion materials; Figure A shows the results of different Pr values ​​after calcination at 900℃. 3 + Doping concentration Pr 3+ XRD patterns of Y₂SiO₅ samples, with standard Y₂SiO₅ diffraction pattern (PDF#52-1810) as a reference; B represents different Pr 3+ Doping concentration Pr 3+ FTIR spectra of Y2SiO5 samples; C represents Pr3+ doping concentrations under 450nm excitation. 3+ Upconversion emission spectrum of Y2SiO5 sample; D represents Ag@Pr 3+ XRD patterns of Y2SiO5 samples, Ag@Pr:YSO-1 to Ag@Pr:YSO-6 represent Ag-modified Pr samples prepared with different amounts of AgNO3 and trisodium citrate. 3+ The sample was Y₂SiO₅, with standard diffraction patterns of Y₂SiO₅ (PDF#52-1810) and Ag (PDF#04-0783) used as controls; E represents Ag@Pr 3+ FTIR spectrum of Y2SiO5 sample; F is the Pr excitation at 450 nm. 3+ Y2SiO5 and Ag@Pr 3+ Upconversion emission spectrum of Y2SiO5 sample; Figure 2 For Ag@Pr 3+ XPS full spectrum analysis results of Y2SiO5.

[0022] Figure 3 For Ag@Pr 3+ : The ultraviolet-visible absorption spectrum of Y2SiO5.

[0023] Figure 4The figures show the morphological characterization results of the upconversion material; A in the figure represents Pr. 3+ TEM images of Y₂SiO₅, scale bars at 200 nm and 20 nm; B represents Ag@Pr 3+ TEM images of Y₂SiO₅, scale bars at 200 nm and 20 nm; C represents Ag@Pr 3+ TEM image, HAADF-STEM image, elemental mapping of Ag, Pr, Y, Si and O, and comprehensive color elemental mapping of Y2SiO5, scale bar 100nm.

[0024] Figure 5 The figure shows the preparation and performance characterization results of the visible light-activated upconversion thermosensitive hydrogel; Figure A represents the thermosensitive hydrogel network formed by HTCC, β-GP, and HEC, and Ag@Pr 3+ A: Schematic diagram of Y2SiO5 particle loading; B: Photographs of the sol-gel transition of the hydrogel precursor solution under low temperature conditions and after incubation at 37°C; C: Rheological analysis of storage modulus (G') and loss modulus (G'') as a function of temperature during the sol-gel transition; D: Oscillation frequency scanning results of the formed upconversion thermosensitive hydrogel; E: FTIR spectra of pure hydrogel and upconversion thermosensitive hydrogel; F: SEM image of the porous microstructure of pure hydrogel, scale bar 200 μm; G: SEM image of the porous microstructure of upconversion thermosensitive hydrogel, scale bar 200 μm; H: Adhesion properties of upconversion thermosensitive hydrogel on different substrates such as paper, glass, muscle, skin, heart, and kidney; I: Adhesion, deformability, and removability of upconversion thermosensitive hydrogel on pigskin, including bending, twisting, folding, and peeling with tweezers; J: Schematic diagram of possible interfacial adhesion mechanism of upconversion thermosensitive hydrogel.

[0025] Figure 6 Photographs of the gelation behavior of visible light-activated upconversion thermosensitive hydrogels at low temperature and 37°C.

[0026] Figure 7 The results show the biocompatibility and photoactivated cytotoxicity evaluation of the visible light-activated upconversion thermosensitive hydrogel. In the figure, AC represents the cell viability (n=5) of HaCaT cells, DC2.4 dendritic cells, and T cells after incubation for 24 h under light-protected conditions using the CCK-8 assay; DF represents the cell viability (n=5) of HaCaT cells, DC2.4 cells, and T cells after treatment with different concentrations of the upconversion thermosensitive hydrogel system under conditions with and without visible light irradiation; G and H represent representative colony images of *Escherichia coli* and *Staphylococcus aureus* in different treatment groups under light-protected or visible light irradiation conditions; I is a schematic diagram of visible light-triggered photoconversion and subsequent UV-induced cell and bacterial damage in the upconversion thermosensitive hydrogel system. Data are expressed as mean ± standard deviation. p <0.0001.

[0027] Figure 8 The therapeutic effect of visible light-activated upconversion thermosensitive hydrogel on IMQ-induced psoriasis-like mouse skin lesions is shown in the figure. Figure A shows the experimental timeline and treatment protocol; B shows the dynamic changes in erythema, scaling, and skin thickening scores during treatment (n=6); C shows the total PASI scores of mice in different treatment groups (n=6); D shows representative photographs of back skin lesions on day 7; E shows representative photographs of spleens collected from different treatment groups (n=4); F shows representative H&E staining and immunohistochemical staining of Ki67, NF-κB p65, and CD45 in back skin tissue, scale bar 100 μm; G shows quantitative analysis of epidermal thickness based on H&E staining (n=5); H shows the relative mRNA expression levels of Tnf-α, Il-1β, Il-17f, and Cxcl10 in skin tissue detected by qRT-PCR (n=6). Data are expressed as mean ± standard deviation; ns, no statistically significant difference. p <0.01; p <0.001.

[0028] Figure 9 For quantitative analysis of spleen weight in mice from different treatment groups (n=4); Figure p <0.01; Healthy represents the healthy group, IMQ represents the model group, IMQ+Light represents the IMQ+light group, IMQ+Hydrogel represents the IMQ+hydrogel group, IMQ+Hydrogel+Light represents the IMQ+hydrogel+light group, and IMQ+Calcipotriol represents the IMQ+calcipotriol group.

[0029] Figure 10 The figure shows the dynamic changes in body weight of mice in each group during the treatment period (n=6); Healthy represents the healthy group, IMQ represents the model group, IMQ+Light represents the IMQ+light group, Hydrogel represents the IMQ+hydrogel group, IMQ+Hydrogel+Light represents the IMQ+hydrogel+light group, and Calcipotriol represents the IMQ+calcipotriol group.

[0030] Figure 11Images of H&E staining of major organs (heart, liver, spleen, lung, and kidney) in mice from different treatment groups; Healthy represents the healthy group, IMQ represents the model group, IMQ+Light represents the IMQ+light group, IMQ+Hydrogel represents the IMQ+hydrogel group, IMQ+Hydrogel+Light represents the IMQ+hydrogel+light group, and IMQ+Calcipotriol represents the IMQ+calcipotriol group. The scale bar is 100 μm.

[0031] Figure 12 This illustrates the remodeling effect of visible light-activated upconversion thermosensitive hydrogel on the local and systemic immune microenvironment of psoriatic lesions; Figure A shows a schematic diagram of immune microenvironment remodeling after treatment with visible light-activated upconversion thermosensitive hydrogel; Figure B shows CD11c in the lesions. + Representative flow cytometry image of dendritic cells; C represents CD11c in skin tissue. + Quantitative analysis of dendritic cells (n=4); D shows the quantitative analysis and representative histogram of CD86 expression in dendritic cells (n=4), MFI represents the mean fluorescence intensity; E shows the expression of CD11b in skin tissue. + Ly6G + Quantitative analysis of neutrophils (n=4); F represents CD11b + Ly6G + Representative flow cytometry image of neutrophils; G represents CD11b. + F4 / 80 + Representative flow cytometry image of macrophages; H represents CD11b in skin tissue. + F4 / 80 + Quantitative analysis of macrophages (n=4); I represents CD45 in skin tissue. + CD3 + Quantitative analysis of T cells (n=4); J represents CD3 in skin tissue. + CD4 + Quantitative analysis and representative histogram of Foxp3 expression in T cells (n=4); K and L represent CD3 expression in the spleen. + CD4 + and CD3 + CD8 + Quantitative analysis of T cells (n=4); M and N represent serum IL-17A and IL-23 levels detected by ELISA (n=4); data are expressed as mean ± standard deviation; ns, no statistically significant difference; p <0.05; p <0.01; p <0.001.

[0032] Figure 13 CD45 in skin tissue + CD3 + A representative flow cytometry image of T cells.

[0033] Figure 14 Immunohistochemical staining images of CD103 in skin tissue; G1-G6 in the image correspond to the healthy group, IMQ group, IMQ+light irradiation group, IMQ+hydrogel group, IMQ+hydrogel+light irradiation group and IMQ+calcipotriol group, respectively, with a scale bar of 100 μm.

[0034] Figure 15 Immunohistochemical staining images of TNF-α in skin tissue; G1-G6 in the image correspond to the healthy group, IMQ group, IMQ+light irradiation group, IMQ+hydrogel group, IMQ+hydrogel+light irradiation group and IMQ+calcipotriol group, respectively, with a scale bar of 100 μm.

[0035] Figure 16 Immunohistochemical staining images of IL-17 in skin tissue; G1-G6 in the image correspond to the healthy group, IMQ group, IMQ+light irradiation group, IMQ+hydrogel group, IMQ+hydrogel+light irradiation group and IMQ+calcipotriol group, respectively, with a scale bar of 100 μm.

[0036] Figure 17 CD3 in the spleen + CD4 + Representative flow cytometry diagram of T cells; in the diagram, Healthy represents the healthy group, IMQ represents the model group, IMQ+Light represents the IMQ+light group, IMQ+Hydrogel represents the IMQ+hydrogel group, IMQ+Hydrogel+Light represents the IMQ+hydrogel+light group, and Calcipotriol represents the IMQ+calcipotriol group.

[0037] Figure 18 CD3 in the spleen + CD8 + Representative flow cytometry diagram of T cells; in the diagram, Healthy represents the healthy group, IMQ represents the model group, IMQ+Light represents the IMQ+light group, IMQ+Hydrogel represents the IMQ+hydrogel group, IMQ+Hydrogel+Light represents the IMQ+hydrogel+light group, and Calcipotriol represents the IMQ+calcipotriol group.

[0038] Figure 19The transcriptome analysis results are shown below after treatment with visible light-activated upconversion thermosensitive hydrogel. Figure A is the PCA diagram of RNA sequencing results from the normal group, IMQ group, and hydrogel + light-induced group; B is the volcano diagram of differentially expressed genes between the hydrogel + light-induced group and the IMQ group, with red and blue dots representing significantly upregulated and significantly downregulated genes, respectively; C and D are GSEA diagrams, showing negative enrichment of cell cycle and DNA replication pathways after hydrogel + light-induced treatment; E is a GSEA diagram, showing positive enrichment of the PPAR signaling pathway; F is a GSEA diagram, showing negative enrichment of the gene set integrating IL-17A signaling. Detailed Implementation

[0039] This invention provides the application of a visible light-activated upconversion thermosensitive hydrogel in the preparation of a drug for treating psoriasis. The visible light-activated upconversion thermosensitive hydrogel is prepared by the following method: (1) Preparation of Pr 3+ Y2SiO5 nanoparticles, for the Pr 3+ Y2SiO5 nanoparticles were modified with amino groups. (2) The amino-modified Pr 3+ Y₂SiO₅ nanoparticles were dispersed in water and heated to 90-110℃. An aqueous solution of silver nitrate and KH-550 was added, and the mixture was stirred. Then, trisodium citrate solution was added dropwise. The precipitate was collected, washed, and dried to obtain Ag@Pr 3+ Y2SiO5 upconversion material; (3) Quaternized chitosan, β-glycerol phosphate and hydroxyethyl cellulose were mixed under ice bath conditions to obtain a thermosensitive hydrogel precursor solution; the Ag@Pr obtained in step (2) was then mixed with the quaternized chitosan, β-glycerol phosphate and hydroxyethyl cellulose to obtain a thermosensitive hydrogel precursor solution. 3+ Y2SiO5 upconversion material is dispersed in the thermosensitive hydrogel precursor solution and mixed evenly to obtain the visible light activated upconversion thermosensitive hydrogel.

[0040] The Ag@Pr of this invention 3+ In Y2SiO5 upconversion materials, Pr 3+ The preparation and amino modification of Y₂SiO₅ nanoparticles are key steps in constructing the core luminescent centers of upconversion materials. Firstly, Pr was prepared via the sol-gel method. 3+ The doped yttrium silicate nanoparticles were specifically prepared by dissolving yttrium oxide and praseodymium nitrate in dilute nitric acid, adding tetraethyl orthosilicate, forming a gel in a 70°C water bath, drying, and then calcining in an oxygen atmosphere at 900°C to obtain Pr with good crystallinity. 3+ Y2SiO5 nanoparticles, in which Pr 3+The molar amount of doping in the matrix is ​​controlled within the range of 1%-5%, more preferably 5%. To achieve stable loading of silver ions, the nanoparticles need to be surface-modified with amino groups. This is done by dispersing the obtained nanoparticles in a weakly acidic aqueous solution containing acetic acid, adding 15-25 μL of KH-550 silane coupling agent, and stirring thoroughly at room temperature to couple the amino groups to the particle surface. After centrifugation and washing with deionized water, the nanoparticles are redispersed in water to obtain amino-modified Pr. 3+ Y₂SiO₅ suspension, which is used for subsequent reaction with silver nitrate to prepare Ag@Pr 3+ Y₂SiO₅ provides the reaction precursor. The above method ensures that Pr 3+ Effective doping of Pr with ions 3+ The Y₂SiO₅ crystal lattice forms luminescent centers, while simultaneously introducing uniformly distributed amino active sites on the particle surface, which are Ag. + This provides a basis for chemical anchoring. The present invention provides a basis for Pr 3+ The doping concentration and amino modification conditions do not need to be strictly limited, and those skilled in the art can optimize and adjust them through routine experiments according to actual needs.

[0041] The Ag@Pr of this invention 3+ In Y₂SiO₅ upconversion materials, surface modification with silver ions is a key step in enhancing upconversion luminescence performance. The above-mentioned amino-modified Pr 3+ Y₂SiO₅ nanoparticles were redispersed in deionized water and transferred to an oil bath, then heated to 90-110°C, preferably 100°C, to obtain a homogeneous suspension. Subsequently, an aqueous solution containing silver nitrate and KH-550 was added sequentially to the suspension. KH-550 not only acts as a dispersant to prevent particle aggregation but also reacts with Ag through its amino groups. + The coordination between them promotes the uniform anchoring of silver ions on the particle surface. After stirring for a certain period of time, trisodium citrate solution is slowly added dropwise. Under heating conditions, trisodium citrate exerts a mild reducing effect, causing the Ag adsorbed on the particle surface to be removed. + In-situ reduction yields silver nanostructures, while citrate ions act as stabilizers to control the size and dispersion of silver particles. After dropwise addition, stirring continues to ensure complete reaction. Once the reaction is finished, the precipitate is collected and repeatedly washed with deionized water to remove unreacted raw materials and byproducts. Finally, vacuum drying yields Ag@Pr. 3+ Y₂SiO₅ upconversion material. By adjusting the ratio of silver nitrate and trisodium citrate, the loading and particle size of the silver nanostructures can be optimized, thereby achieving the best upconversion luminescence enhancement effect. The Ag@Pr described in this invention... 3+The Y₂SiO₅ upconversion material emits ultraviolet light with wavelengths of 297-319 nm under 450 nm visible light excitation. This performance was tested using a fluorescence spectrometer equipped with a continuous-wave laser, with an excitation wavelength of 450 nm, an emission spectrum scanning range of 250-500 nm, and a slit width of 2 nm. The test results showed that the material exhibits distinct and sharp emission peaks at 297 nm, 308 nm, and 319 nm. These ultraviolet emission wavelengths match the therapeutic window of narrow-spectrum UVB phototherapy for psoriasis, indicating that the material can convert visible light into therapeutically effective ultraviolet light.

[0042] The preparation of the upconversion thermosensitive hydrogel described in this invention is a key step in constructing a phototherapy interface that can adhere to the lesion. The preferred preparation steps are as follows: Quaternized chitosan (HTCC) is dissolved in a weakly acidic aqueous solution to prepare a 2% (w / v) stock solution. Separately, β-glycerophosphate is dissolved in deionized water to prepare a 0.4 g / mL solution, and hydroxyethyl cellulose is dissolved in deionized water to prepare a 0.15 g / mL solution. The three solutions are pre-cooled at 4°C for 30 min. Under ice bath conditions, the β-glycerophosphate solution is slowly added dropwise to the quaternized chitosan solution while stirring, followed by the hydroxyethyl cellulose solution. The mixture is kept in an ice bath and stirred continuously for 15 min to ensure uniform mixing of the components, resulting in a homogeneous and transparent thermosensitive hydrogel precursor solution. This precursor solution maintains a flowable sol state at low temperatures. The aforementioned Ag@Pr 3+ The Y₂SiO₅ upconversion material dispersion is slowly added to the precursor solution under stirring. The final concentration of the upconversion material in the gel is controlled at 0.5-1 mg / mL. Thorough stirring ensures uniform dispersion of the upconversion particles in the gel matrix, resulting in a visible light-activated upconversion thermosensitive hydrogel. The resulting hydrogel is a coatable sol-gel at low temperatures, facilitating local application. When the temperature rises to 32-37°C, the system undergoes a sol-gel transition within approximately 5 minutes, forming a semi-solid gel with certain mechanical strength, thereby stably fixing the upconversion material at the application site. The method of this invention is simple to operate, operates under mild conditions, and is beneficial for maintaining the optical properties of the upconversion material.

[0043] The visible light-activated upconversion thermosensitive hydrogel of this invention exerts its therapeutic effect on psoriasis through the following mechanism: Flow cytometry analysis of immune cell subsets in psoriatic lesions after treatment showed that after hydrogel + phototherapy, CD11c levels in the lesions increased. + The proportion of dendritic cells decreased from 19.0% to 7.77%, and the expression of the co-stimulatory molecule CD86 was significantly reduced, while CD11b... + Ly6G + Neutrophils decreased from 51.1% to 26.4%, CD11b + F4 / 80 +The proportion of macrophages also decreased significantly, CD45 + CD3 + T-cell infiltration was reduced. ELISA results showed that hydrogel + phototherapy significantly reduced serum IL-17A and IL-23 levels. These results indicate that the drug treats psoriasis by inhibiting the IL-23 / IL-17 inflammatory pathway. RNA sequencing and gene set enrichment analysis showed that after hydrogel + phototherapy, both cell cycle pathways (NES=-2.58, FDR<0.001) and DNA replication pathways (NES=-2.49, FDR<0.001) showed significant negative enrichment, indicating that the drug inhibits excessive keratinocyte proliferation by downregulating cell cycle and DNA replication-related pathways. The absolute upconversion photoluminescence quantum yield was measured using a fluorescence spectrometer equipped with an integrating sphere. The results showed that the upconversion quantum yield of the visible light-activated thermosensitive hydrogel under visible light irradiation was ≥10%, specifically reaching 10.92%, ensuring high light conversion efficiency and therapeutic light intensity.

[0044] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0045] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples are commercially available products. In the following examples, tetraethyl orthosilicate, praseodymium nitrate hexahydrate, silane coupling agent (KH-550), nitric acid, sodium β-glycerophosphate, and hydroxyethyl cellulose were purchased from Aladdin Reagent Co., Ltd. (Shanghai, China). Silver nitrate and anhydrous ethanol were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Yttrium oxide was purchased from Shanghai Mainano Materials Technology Co., Ltd. Trisodium citrate was purchased from Bid Pharmaceutical Technology Co., Ltd. (Shanghai, China). Quaternized chitosan was purchased from Wuhan Lanabai Pharmaceutical Chemical Co., Ltd. (Wuhan, China). All chemical reagents were used directly without further purification. All aqueous solutions were prepared with ultrapure deionized water. Cell counting kit-8 (CCK-8) was purchased from Beyotime Biotechnology Co., Ltd. (Shanghai, China). All fluorescently labeled antibodies used in flow cytometry were purchased from BioLegend (San Diego, California, USA). DC2.4 dendritic cells, RAW264.7 macrophages, HaCaT keratinocytes, and the human T-lymphocytic leukemia cell line 6T-CEM were all purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Cells were cultured in RPMI 1640 medium or Dulbecco modified Eagle medium (DMEM) containing 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin (PS), and incubated at 37°C in a humidified incubator with 5% CO2. Cell passage or subsequent experiments were performed when cell confluence reached 70%-80%.

[0046] Example 1 Ag@Pr 3+ Preparation of Y2SiO5 upconversion materials This embodiment provides an Ag@Pr 3+ The preparation method of Y2SiO5 upconversion material is as follows: (1) Pr 3+ Preparation of Y2SiO5 nanoparticles A 0.1 mol / L praseodymium nitrate solution [Pr(NO3)3] was prepared. 0.663 g of yttrium oxide (Y2O3) was placed in a beaker, and a 1:1 volume ratio of dilute nitric acid and water was added. The praseodymium nitrate solution was then added to the mixture using a pipette, and the beaker was sealed with plastic wrap. The beaker was placed in an 80°C water bath to promote dissolution. After the solid was completely dissolved, the solution was heated on a hot plate to evaporate the solvent until the solution became viscous. After heating was stopped, the solution was allowed to cool naturally, during which a large number of crystals formed. The resulting sample was dried at 104°C. The dried sample was then added to a 1:3 volume ratio of distilled water and anhydrous ethanol to promote dissolution. After the sample was completely dissolved, tetraethyl orthosilicate (TEOS) was added, and the mixture was stirred for approximately 25 min. The resulting mixture was then placed in a 70°C water bath to form a gel. The gel was dried at 104°C and ground into powder using a mortar and pestle. Finally, calcination was carried out in a muffle furnace according to a programmed heating method. The heating rate was set to 8℃ / min, and after reaching 900℃, it was held for 3 hours to obtain Pr. 3+ Y₂SiO₅ nanoparticles. Among them, Pr 3+ The molar doping amount in Y2SiO5 is 5%.

[0047] (2) Amino modification 0.02 mmol Pr 3+ Y₂SiO₅ was dispersed in an aqueous acetic acid solution. Then, 20 μL of KH-550 was added. After stirring for 4 h, the amino-modified sample was collected by centrifugation, washed twice with deionized water, and finally redispersed in deionized water to obtain Pr. 3 + :Y2SiO5 suspension.

[0048] (3) Ag@Pr 3+ Preparation of Y2SiO5 upconversion materials The Pr prepared in step (2) 3+The Y₂SiO₅ suspension was heated to 100℃, and then 0.0036 mol of silver nitrate and 20 μL of KH-550 aqueous solution were added sequentially. After stirring for 20 min, 0.0004 mol of trisodium citrate aqueous solution was added dropwise, and stirring was continued for another 20 min. The precipitate was then collected, washed 6 times with deionized water, and dried under vacuum at 70℃ for 24 h.

[0049] Example 2 Ag@Pr 3+ Characterization of Y2SiO5 upconversion materials This embodiment describes the Ag@Pr prepared in Example 1. 3+ Characterization of the Y₂SiO₅ upconversion material was performed. Specifically, the morphology of the samples was characterized using scanning electron microscopy and transmission electron microscopy. The crystal structure was analyzed using X-ray diffraction. The chemical structure was characterized using Fourier transform infrared spectroscopy. The emission spectra were recorded using fluorescence spectroscopy.

[0050] To optimize the Ag modification conditions, Pr is fixed. 3+ The amount of Y2SiO5 was 0.02 mmol. Silver nitrate and trisodium citrate were added according to different feed amounts shown in Table 1 to prepare six groups of samples, from Ag@Pr:YSO-1 to Ag@Pr:YSO-6.

[0051] Table 1 Ag@Pr under different Ag modification conditions 3+ Preparation ratio of Y2SiO5 sample

[0052] 1. Pr was analyzed using X-ray diffraction (XRD). 3+ Crystal structure of Y2SiO5 When the calcination temperature is increased to 900℃, Pr 3+ The diffraction peaks of samples with doping concentrations of 0%-5% all showed high agreement with the standard Y₂SiO₅ crystal phase (PDF#52-1810), confirming the formation of crystalline Y₂SiO₅. Figure 1 (A) In comparison, 8%Pr 3+ The broadened and weakened diffraction peaks of the doped sample indicate excessive Pr. 3+ The introduction of [something] may interfere with crystal formation or reduce phase purity.

[0053] 2. Fourier transform infrared spectroscopy (FTIR) was used to verify the formation of the yttrium silicate framework. All Pr 3+ Y2SiO5 samples at 500-1200 cm⁻¹ -1 The fingerprint areas all exhibit characteristic absorption bands ( Figure 1 (Medium B). Approximately 550cm -1The absorption bands at 844, 928, and 1011 cm⁻¹ can be attributed to YO-related lattice vibrations, accompanied by low-frequency Si-O bending vibrations. -1 The absorption band at 844 cm⁻¹ is a characteristic peak of the silicate framework. -1 The absorption band at 928 cm⁻¹ is related to the Si-O stretching vibration inside the SiO₄ tetrahedron; -1 The peak at 10¹¹ cm⁻¹ corresponds to the fundamental stretching vibration of Si-O; -1 The absorption bands at these locations can be attributed to high-frequency Si-O stretching vibrations, including Si-OY or Si-O-Si related asymmetric stretching vibrations. These characteristic absorption bands confirm the successful formation of the Y2SiO5 framework structure after calcination. Subsequently, Pr was evaluated under 450 nm excitation conditions. 3+ The upconversion luminescence properties of Y₂SiO₅. For example... Figure 1 As shown in C, Pr 3+ The emission spectrum of Y₂SiO₅ is mainly distributed in the ultraviolet band of approximately 280-340 nm, indicating that it has visible-to-ultraviolet upconversion emission capability. When Pr 3+ At a doping concentration of 0.5%, the emission intensity is relatively weak. With Pr 3+ With increasing concentration, ultraviolet emission is significantly enhanced, especially in 5% Pr 3+ The doped sample exhibited the strongest emission intensity. However, when Pr 3 + When the doping concentration was further increased to 8%, the emission intensity actually decreased. This may be related to concentration quenching and adjacent Pr 3+ This is related to enhanced nonradiative energy migration between ions and decreased crystallinity due to excessively high doping levels. Therefore, 5% Pr was chosen. 3+ This serves as the optimal doping concentration for subsequent Ag modification.

[0054] 3. XRD was used to analyze Ag@Pr 3+ The crystal structure of Y2SiO5 was characterized. like Figure 1 As shown in Figure D, the characteristic diffraction peaks of Y₂SiO₅ (PDF#52-1810) were retained after Ag modification, indicating that the matrix crystal framework was not damaged. Simultaneously, characteristic diffraction peaks corresponding to crystalline Ag (PDF#04-0783) were observed, confirming the successful introduction of the Ag species. The coexistence of Y₂SiO₅ and Ag diffraction signals indicates that Ag mainly exists as a surface modification phase, rather than being substituted into the Y₂SiO₅ lattice. Ag@Pr 3+ FTIR results of Y2SiO5 further confirmed that the silicate framework structure was still preserved after Ag modification. Figure 1The characteristic vibrational absorption bands of YO and Si-O are still clearly visible, indicating that Ag modification did not destroy the Y2SiO5 matrix structure. After Ag modification, the characteristic vibrational absorption bands at approximately 1558 cm⁻¹ are still visible. -1 The observed weak absorption band can be attributed to the NH bending vibration generated by the amino-containing modifiers introduced during the synthesis process. These amino groups may promote Ag anchoring on the particle surface through electrostatic interactions or coordination with Ag species.

[0055] 4. X-ray photoelectron spectroscopy (XPS) was used to analyze Ag@Pr 3+ Surface chemical composition and elemental valence states of Y2SiO5.

[0056] Full spectrum results confirmed the presence of Ag, Pr, Y, Si, and O elements in the sample, consistent with the expected composition. Figure 2 The UV-Vis absorption spectrum shows that the material has a broad absorption band at approximately 450 nm. Figure 3 Under 450 nm excitation conditions, compared with unmodified Pr 3+ Compared to Y2SiO5, Ag@Pr 3+ Y2SiO5 exhibits significantly enhanced ultraviolet emission ( Figure 1 (Middle F). Distinct emission peaks were observed at approximately 297, 308, and 319 nm, wavelengths within the UV range associated with phototherapy for psoriasis. Ag@Pr:YSO-1 was used in subsequent experiments because it exhibited the highest UV emission intensity.

[0057] 5. Absolute upconversion photoluminescence quantum yield was determined using an Edinburgh Instruments FLS1000 fluorescence spectrometer equipped with an integrating sphere. The results show that the quantum yield increased from Pr 3+ The content of Y2SiO5 was increased from 3.95% to Ag@Pr 3+ The content of Y₂SiO₅ was 10.92%, an increase of approximately 2.8 times. This result further confirms that Ag modification can effectively improve the visible-to-ultraviolet upconversion efficiency.

[0058] 6. Observation of Ag@Pr using transmission electron microscopy (TEM) 3+ morphology of Y2SiO5 The results showed that Pr 3+ Y2SiO5 particles are slender and have a relatively smooth surface. Figure 4 (A). After Ag modification, the overall morphology of the particles remained basically unchanged, but the surface became significantly rougher, and multiple small nanostructure domains appeared, consistent with the characteristics of Ag distribution on the particle surface. Figure 4 (B). Element mapping results show that Ag, Pr, Y, Si, and O elements are mapped in Ag@Pr3+ The Y2SiO5 particles are evenly distributed. Figure 4 (C), further confirming Ag modification of Pr 3+ The successful preparation of Y₂SiO₅ was achieved. In summary, the structural, chemical composition, optical properties, and morphological characterization results collectively demonstrate the successful construction of Ag@Pr with enhanced visible-to-ultraviolet upconversion luminescence properties. 3+ :Y2SiO5.

[0059] Example 3: Preparation of Visible Light-Activated Upconversion Thermosensitive Hydrogel This embodiment provides a method for preparing a visible light-activated upconversion thermosensitive hydrogel, the steps of which are as follows: A 2% (w / v) solution of quaternized chitosan, an aqueous solution of sodium β-glycerophosphate (0.4 g / mL), and a solution of hydroxyethyl cellulose (0.15 g / mL) were pre-cooled at 4°C for 30 min. While stirring in an ice-water bath, the sodium β-glycerophosphate aqueous solution was slowly added dropwise to the chitosan solution, followed by the addition of hydroxyethyl cellulose. Stirring was continued in the ice-water bath for 15 min to obtain a chitosan / sodium β-glycerophosphate / hydroxyethyl cellulose mixed solution (HTCC / β-GP / HEC mixed solution). The mass ratio of quaternized chitosan, β-glycerophosphate, and hydroxyethyl cellulose was 1:2:1.

[0060] The Ag@Pr prepared in Example 1 3+ The Y2SiO5 upconversion material was redispersed in anhydrous ethanol to obtain Ag@Pr 3+ Y2SiO5 upconversion material dispersion; add the obtained dispersion to the above mixed solution and stir thoroughly until homogeneous. Figure 5 (A) to obtain a visible light-activated upconversion thermosensitive hydrogel.

[0061] Example 4: Characterization and performance testing of visible light-activated upconversion thermosensitive hydrogels This embodiment characterizes and tests the performance of the visible light-activated upconversion thermosensitive hydrogel prepared in Example 3, specifically including: characterizing the morphology of the thermosensitive hydrogel using SEM; evaluating its mechanical properties using a rheometer; and analyzing its chemical structure using FTIR.

[0062] 1. Rheological analysis was used to study the sol-gel transition process of upconversion thermosensitive hydrogels. The HTCC / β-GP / HEC precursor solution maintains a flowable sol state at low temperatures, which is beneficial for Ag@Pr 3+ The uniform mixing and convenient local coating of Y₂SiO₅ were achieved. When heated to 37°C, the transparent precursor solution gradually transformed into a non-flowing hydrogel within approximately 5 minutes. Figure 5(B) Notably, no significant turbidity was observed during gelation, indicating that the hydrogel matrix maintained good optical transparency. This property facilitates the penetration of visible light into the hydrogel and its absorption by the embedded Ag@Pr 3+ Y2SiO5 particles absorb the substance. Ag@Pr is added. 3+ After Y2SiO5, the hydrogel's appearance darkens due to the color of the upconversion particles themselves, but it still maintains good temperature-responsive gelation behavior. Figure 6 ).

[0063] During the temperature scan, the loss modulus (G'') was higher than the storage modulus (G') at low temperatures, indicating that the precursor solution exhibited liquid-like characteristics. As the temperature increased, G' increased rapidly and exceeded G'' at approximately 37°C, indicating the formation of a cross-linked hydrogel network and a transition from sol to gel. Figure 5 (C). This transition temperature is close to physiological skin temperature, supporting in-situ gelation of the formulation after topical application. Temperature-induced gelation of the chitosan / β-GP system is generally attributed to electrostatic interactions, hydrogen bonding, and enhanced hydrophobic association upon heating. Further evaluation of the formed Ag@Pr was conducted using oscillation frequency scanning. 3+ The viscoelasticity of Y₂SiO₅ hydrogel. In the angular frequency range of 0.1-100 rad / s, G' is consistently higher than G'', confirming that the hydrogel exhibits predominantly elastic and solid-like behavior. Figure 5 (D). As the frequency increases, both G' and G'' gradually increase, indicating that the system forms a dynamic cross-linked network capable of resisting deformation. This viscoelastic stability is of great significance for maintaining the stable adhesion of the hydrogel to curved or active skin surfaces.

[0064] 2. FTIR analysis of the chemical interactions within the upconversion thermosensitive hydrogel system. like Figure 5 The results from the E-test show that the load Ag@Pr 3+ After Y₂SiO₅ treatment, the characteristic absorption peaks of the hydrogel matrix are retained, while new absorption signals or enhanced absorption intensities appear in the fingerprint region related to the Si-O and YO-Si vibrations of yttrium silicate particles. The internal microstructure of the hydrogel is observed using SEM. Pure hydrogel and Ag@Pr 3+ Y2SiO5 hydrogels all exhibit an interconnected porous three-dimensional network structure. Figure 5 China F and Figure 5 The presence of Ag@Pr (a type of hydrogel) is beneficial for moisture retention, material flexibility, and sufficient contact with the skin interface. Compared to pure hydrogels, Ag@Pr 3+The Y₂SiO₅ hydrogel exhibits a denser porous structure and smaller pore size, suggesting that inorganic particles may participate in the formation of the hydrogel network or enhance it. This denser structure may contribute to improving the mechanical stability of the hydrogel and enhancing the retention capacity of upconversion particles in the gel matrix.

[0065] 3. Performance testing of upconversion thermosensitive hydrogels The hydrogel prepared by this invention can firmly adhere to the surfaces of paper, glass, and various biological tissues, and its adhesive force is sufficient to support the weight of these substrates. Figure 5 (H). To further simulate the application of hydrogel on soft, deformable skin, it was applied to the surface of pigskin. After bending, twisting, and folding, the hydrogel remained firmly attached to the skin surface without significant detachment. Furthermore, the formed hydrogel film could be peeled off from the edges with tweezers, indicating good removability after treatment. Figure 5 (I). This deformable and adhesive property is particularly important for the treatment of psoriasis because psoriatic plaques are often located in curved, mobile, or irregularly shaped anatomical sites. The adhesiveness of hydrogels may originate from a variety of interfacial interactions, including hydrogen bonds formed between hydroxyl / amino groups and tissue surface groups, electrostatic interactions mediated by cationic HTCC chains, hydrophobic interactions, and physical intercalation with moist tissue surfaces. Figure 5 (J).

[0066] In summary, the upconversion thermosensitive hydrogel (Ag@Pr) prepared by this invention... 3+ Y2SiO5 thermosensitive hydrogel has body temperature-triggered gelation, good optical compatibility, porous network structure and strong tissue adhesion ability, supporting its application as a phototherapy interface that can adhere to lesions.

[0067] Experimental Example 1: Biocompatibility and Photoactivated Cytotoxicity of Upconversion Thermosensitive Hydrogel 1. Cytotoxicity evaluation of upconversion thermosensitive hydrogels The cytotoxicity of the upconversion thermosensitive hydrogels prepared in Example 3 was evaluated using the CCK-8 assay. Hydrogels loaded with different concentrations of Ag@Pr were then used. 3+ Thermosensitive hydrogels of Y₂SiO₅ (0, 15.6, 31.25, 62.5, 125, 250, 500, 1000 μg / mL) were added to complete culture medium at a ratio of 0.1 g / mL and soaked at 37℃ for 24 h. The supernatant was collected to obtain the thermosensitive hydrogel extracts of different concentration gradients. HaCaT cells were then cultured at 7 × 10⁶ cells / well. 3Cells were seeded at a density of 100 μL in 96-well plates and cultured in a humidified incubator containing 5% CO2 for 24 h. The culture medium was then replaced with an upconversion thermosensitive hydrogel extract and incubated for another 24 h in the dark. After discarding the culture medium, cells were washed twice with PBS. Then, 100 μL of 10% CCK-8 working solution diluted with serum-free DMEM was added to each well and incubated for 2 h. The absorbance at 450 nm was measured using a microplate reader. The cytotoxicity of the upconversion thermosensitive hydrogel to DC2.4 cells and T cells was evaluated using a similar procedure. Photoinduced cytotoxicity was evaluated using a Transwell co-culture system. Cells were seeded in the lower chamber of a Transwell and cultured for 24 h to promote cell adhesion. Then, the upconversion thermosensitive hydrogel (loaded with Ag@Pr) was added to each well. 3+ A hydrogel of Y₂SiO₅ was placed in the upper chamber of a Transwell apparatus. The hydrogel in the upper chamber was irradiated with 450 nm visible light from above for 30 min. After irradiation, the cells were cultured for another 24 h, and cell viability was assessed using the CCK-8 assay as described above.

[0068] The results are as follows Figure 7 As shown in the AC diagram, after 24 hours of incubation at relatively low and moderate concentrations, the viability of various cell types remained good. In particular, when the upconversion thermosensitive hydrogel concentration did not exceed 500 μg / mL, the survival rates of HaCaT cells, DC2.4 cells, and T cells remained above approximately 85%, indicating that the system has good cell compatibility within the concentration range relevant to subsequent photoactivation therapy. Since excessive proliferation of keratinocytes is a major characteristic of epidermal hyperplasia in psoriatic arthritis, the photoactivation inhibitory effect of the upconversion thermosensitive hydrogel system was further evaluated in HaCaT cells. Under light-protected conditions, the upconversion thermosensitive hydrogel at a concentration of 500 μg / mL showed only limited cytotoxicity; however, after exposure to visible light, the viability of HaCaT cells at the same concentration significantly decreased to approximately 60%. Figure 7 (D). This phototoxicity may be related to visible-to-ultraviolet upconversion, where externally applied visible light is converted into localized ultraviolet emission with wavelengths within the therapeutically effective ultraviolet range. Further evaluation of the system's photoactivated immunomodulatory potential in DC2.4 cells and T cells, both of which are involved in amplifying psoriasis-associated inflammatory responses, was conducted. In psoriasis, dendritic cells can activate IL-23 and IL-12-related immune responses, promoting pathogenic T cell activation and excessive keratinocyte proliferation. Compared to light-protected conditions, visible light irradiation in the presence of an upconversion thermosensitive hydrogel significantly and in a concentration-dependent manner reduced the viability of DC2.4 cells and T cells (D). Figure 7 China E and Figure 7(F). When the upconversion thermosensitive hydrogel concentration was 500 μg / mL, the survival rates of DC2.4 cells and T cells decreased to approximately 50% and 40%, respectively. These results indicate that the upconversion thermosensitive hydrogel system can exert a phototoxic effect on demand, activating epidermal cells and immune cells involved in the inflammatory response of psoriasis.

[0069] 2. Antibacterial activity test of upconversion thermosensitive hydrogel The antibacterial activity of this light conversion system was evaluated using *Escherichia coli* (representative of Gram-negative bacteria) and *Staphylococcus aureus* (representative of Gram-positive bacteria). Bacteria were co-incubated with the upconversion thermosensitive hydrogel prepared in Example 3, and divided into a light-protected group and a visible light irradiation group. After irradiation, bacterial suspensions were plated on agar plates and incubated overnight at 37°C for colony counting.

[0070] Plate count results showed that a large number of bacteria grew under dark conditions; however, visible light irradiation in the presence of the upconversion thermosensitive hydrogel significantly reduced the number of bacterial colonies. Figure 7 China G and Figure 7 (H). Notably, after light exposure, Escherichia coli colonies were almost completely eliminated, while the number of Staphylococcus aureus colonies was also significantly reduced. This phototriggered antibacterial effect may be beneficial for the topical treatment of psoriasis, especially considering that inflammatory lesions are often accompanied by impaired skin barrier and microbiome imbalance.

[0071] In summary, the upconversion thermosensitive hydrogel prepared in this invention exhibits good cell compatibility without photoactivation, but after visible light activation, it can produce significant phototoxic effects on keratinocytes, immune cells, and bacteria. Figure 7 (I). This on-demand activation treatment feature helps achieve spatially controlled treatment of psoriatic lesions, that is, local ultraviolet light generation is activated only within the hydrogel-covered area by visible light irradiation, thereby improving lesion selectivity and potentially reducing unnecessary damage to surrounding healthy skin.

[0072] Experiment 2: Establishment of an imiquimod (IMQ)-induced psoriasis-like mouse model and evaluation of the therapeutic effect of upconversion thermosensitive hydrogel. 1. Experimental materials and grouping Male BALB / c mice aged 6-8 weeks were provided by Shanghai Lingchang Biotechnology Co., Ltd. The mice were housed in a standard animal laboratory facility with an ambient temperature maintained at 22±2℃ and a relative humidity of 50%-60%, using a 12h light / 12h dark cycle. The mice had free access to sterilized feed and drinking water. All animal experiments were conducted in accordance with relevant institutional guidelines for the husbandry and use of laboratory animals and were approved by the Animal Ethics Committee of Tongji University (Approval No.: TJAA07722101).

[0073] BALB / c mice were randomly divided into 6 groups: Healthy (G1), IMQ (G2), IMQ+Light (G3), IMQ+Hydrogel (G4), IMQ+Hydrogel+Light (G5), and IMQ+Calcipotriol (G6).

[0074] 2. Establishment and drug administration regimen of a psoriasis-like mouse model Except for the healthy control group, all other groups received topical application of an equal amount of 5% imiquimod (IMQ) cream to the shaved back skin for 8 consecutive days to induce psoriatic skin inflammation. For the treatment group, the upconversion thermosensitive hydrogel formulation prepared in Example 2 was applied to the lesion area every other day, 6 hours after each IMQ administration. The light irradiation group received 450nm LED visible light irradiation for 30 minutes. Calcipotriol was used as a clinically relevant positive control treatment.

[0075] 3. Psoriasis Area and Severity Index (PASI) score The severity of psoriatic lesions was assessed using the Psoriasis Area and Severity Index (PASI) daily before applying IMQ. Erythema, scaling, and thickening were scored from 0 to 4. Mouse weight was recorded every other day. Mice were euthanized at designated time points using CO2 inhalation, and lesioned skin tissue was collected for subsequent analysis. Figure 8 (A) The results are as follows Figure 8 China B and Figure 8 As shown in Figure C, IMQ treatment led to a gradual increase in erythema, scaling, skin thickening, and total PASI score, indicating the successful establishment of the psoriasis-like model. Phototherapy or hydrogel therapy alone showed only limited therapeutic effects. In contrast, the IMQ + hydrogel + phototherapy group (G5) showed significantly reduced erythema, scaling, and skin thickness, and its total PASI score was significantly lower than that of the IMQ group (G2), IMQ + phototherapy group (G3), and IMQ + hydrogel group (G4). The efficacy of IMQ + hydrogel + phototherapy was comparable to that of calcipotriol, indicating that the activation of upconversion thermosensitive hydrogel by visible light is key to its anti-psoriatic effect. Representative photographs of the back skin further confirm the therapeutic effect of the upconversion thermosensitive hydrogel. Figure 8 (D). The light-only group and the hydrogel-only group showed only partial improvement, while the hydrogel + light-only group showed a significant reduction in scaling and erythema, and a smoother skin surface.

[0076] 4. Analysis of spleen morphology and spleen weight After the mice were sacrificed at the end of the experiment, spleens were collected from each group of mice, and their morphology and weight were observed. IMQ treatment led to significant splenomegaly, consistent with immune activation caused by psoriasis-like inflammation. Figure 8 (E). Hydrogel + phototherapy reduced splenomegaly, and quantitative analysis of spleen weight showed that the spleen weight was significantly lower in the hydrogel + phototherapy group compared with the IMQ group. Figure 9 These results suggest that upconversion thermosensitive hydrogels can not only improve local skin lesions, but also reduce IMQ-related systemic immune activation.

[0077] 5. Histological and immunohistochemical analysis At the experimental endpoint, mice were euthanized, and treated dorsal skin tissue and major organs were collected. The collected tissues were fixed in 10% neutral buffered formalin, then embedded in paraffin, and 5 μm thick tissue sections were prepared. Hematoxylin-eosin (H&E) staining was used to evaluate the histopathological changes of the skin lesions and to assess the potential toxicity of the treatment to major organs. ImageJ software was used to quantitatively analyze epidermal thickness.

[0078] For immunohistochemical staining, paraffin-embedded skin sections were dewaxed, rehydrated, and then subjected to heat-induced antigen retrieval in citrate buffer (pH 6.0). After blocking with 5% BSA for 30 min, the sections were incubated overnight at 4°C with specific primary antibodies against CD45, CD103, Ki67, and NF-κB. Subsequently, HRP-conjugated secondary antibody was added and incubated for 1 h at room temperature. The immunoreaction signal was visualized using DAB chromogenic agent, and the cell nuclei were counterstained with hematoxylin. Images were acquired using an Olympus BX43 microscope. H&E staining showed that IMQ induced typical psoriatic pathological changes, including marked acanthosis, hyperkeratosis, epidermal thickening, and elongation of epidermal ridges. Figure 8 Quantitative analysis further showed that, compared with the IMQ group, hydrogel + phototherapy significantly reduced epidermal thickness, suggesting that it can effectively inhibit abnormal epidermal proliferation. Figure 8 Immunohistochemical staining showed that IMQ treatment significantly increased Ki67 expression in the epidermis of mice, reflecting excessive proliferation of keratinocytes; while hydrogel + phototherapy significantly reduced Ki67-positive cells (G). Figure 8 (F). NF-κB p65 staining was significantly enhanced in IMQ-induced lesions, but its expression decreased after hydrogel + phototherapy, suggesting that inflammation-related signals were suppressed. Furthermore, CD45 staining showed a large number of leukocyte infiltrations in IMQ-induced lesions, while leukocyte infiltration was significantly reduced in the hydrogel + phototherapy group. These results indicate that upconversion thermosensitive hydrogels can simultaneously inhibit excessive epidermal proliferation and inflammatory immune cell infiltration.

[0079] 6. Real-time quantitative PCR (RT-qPCR) Total RNA was extracted from skin tissue using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. Briefly, skin samples were homogenized in TRIzol reagent, followed by phase separation with chloroform, RNA precipitation with isopropanol, washing with 75% ethanol, and then dissolving the RNA in nuclease-free water. RNA concentration and purity were determined using a UV spectrophotometer, and RNA quality was evaluated based on the 260 / 280 nm absorbance ratio. cDNA was synthesized using the PrimeScript RT kit (Takara). Real-time quantitative PCR was performed using SYBR Green Master Mix (Applied Biosystems) on a QuantStudio 3 real-time PCR system. Amplification was performed using specific primers targeting the target gene and the internal control gene β-actin. The relative mRNA expression level of the target gene was normalized using β-actin as an internal control, and a 2... ^-ΔΔCt Calculation by method.

[0080] Compared with the IMQ group, hydrogel plus phototherapy significantly downregulated the mRNA expression levels of pro-inflammatory cytokines Tnf-α, Il-1β, and Il-17f, as well as the chemokine Cxcl10. Figure 8 (H). Among them, decreased Il-17f expression is closely related to the core IL-23 / IL-17 inflammatory axis in the pathogenesis of psoriasis; decreased Cxcl10 expression suggests reduced recruitment of inflammatory cells.

[0081] 7. Preliminary assessment of overall safety The systemic safety of the treatment was initially assessed by monitoring body weight and performing histological examinations of major organs. No significant treatment-related weight loss was observed during the treatment period. Figure 10 H&E staining results for the heart, liver, spleen, lungs, and kidneys showed no significant pathological abnormalities after hydrogel + phototherapy. Figure 11 These results indicate that the upconversion thermosensitive hydrogel combined with visible light irradiation exhibits good preliminary biocompatibility in vivo.

[0082] In summary, the visible light-activated upconversion thermosensitive hydrogel prepared in this invention can effectively improve IMQ-induced psoriatic dermatitis, specifically manifested as reduced clinical severity, improved skin appearance, reduced splenomegaly, decreased epidermal hyperplasia, inhibited keratinocyte proliferation, reduced inflammatory cell infiltration, and downregulation of psoriasis-related inflammatory mediators. These results indicate that the upconversion thermosensitive hydrogel has the potential to serve as a localized, lesion-adherent phototherapy platform for psoriasis.

[0083] Experimental Example 3: Effect of Upconversion Thermosensitive Hydrogel on the Remodeling of the Local and Systemic Immune Microenvironment in Psoriatic Lesions To elucidate the immunological mechanism by which visible light-activated upconversion thermosensitive hydrogels exert their therapeutic effects, the local immune microenvironment of psoriatic lesions and systemic immune changes in the spleen were further characterized. Flow cytometry, immunohistochemical staining, and serum cytokine detection were used to evaluate the remodeling of the immune microenvironment after different treatments. Figure 12 (A)

[0084] 1. Experimental Methods (1) Preparation of skin single-cell suspension Skin tissue was cut into 1-2 mm pieces and placed in RPMI 1640 medium containing collagenase I (2 mg / mL), collagenase II (2 mg / mL), collagenase IV (2 mg / mL), and DNase I (50 U / mL). The tissue was digested for 60 min at 37°C and 200 rpm with continuous shaking. The digested tissue was then passed through a 70 μm cell filter to prepare a single-cell suspension.

[0085] (2) Preparation of spleen single-cell suspension For spleen samples, the tissue was minced and gently squeezed through a 70μm cell filter using a syringe plunger. Red blood cells were lysed using red blood cell lysis buffer at room temperature for 3-5 minutes, followed by the addition of PBS to terminate the reaction.

[0086] (3) Flow cytometry staining and detection All cell suspensions were centrifuged at 300×g for 5 min and washed with PBS containing 2% FBS. The resulting cell pellet was resuspended and incubated at 4°C with anti-CD16 / 32 antibody (BioLegend) for 10 min to block Fc receptors. Subsequently, staining was performed using live / dead cell viability dyes and fluorescently conjugated antibodies against CD45, CD11c, CD11b, F4 / 80, MHC-II, CD86, CD80, Ly6G, CD3e, CD4, and CD8a. For intracellular transcription factor staining, cells were fixed and permeabilized according to the manufacturer's instructions and stained with anti-Foxp3 antibody. After washing, cells were resuspended in flow cytometry staining buffer and analyzed using flow cytometry.

[0087] (4) Enzyme-linked immunosorbent assay (ELISA) Whole blood from mice was centrifuged at 4°C and 3000 rpm for 10 min, and serum samples were collected. The levels of mouse IL-17A and IL-23 in the serum were detected using a mouse IL-17A and IL-23 ELISA kit, following the manufacturer's instructions. Samples were added to microplates pre-coated with antibodies and incubated for 2 h. After washing, biotinylated detection antibodies were added and incubated for 1 h, followed by the addition of streptavidin-HRP conjugate and incubation for 30 min. A TMB substrate solution was added for colorimetric reaction, and the reaction was terminated using a stop solution. The absorbance at 450 nm was measured using a microplate reader.

[0088] 2. Results Analysis (1) Results of skin immune cell subset analysis Dendritic cells, by producing IL-23 and IL-12 and further promoting Th17 / Th1-mediated inflammatory responses, are important initiating cells of psoriatic inflammation. Flow cytometry results showed that, compared with the healthy group, CD11c levels in the skin lesions of the IMQ group were significantly higher. + The proportion of dendritic cells increased significantly, from 5.38% to 19.0%. Figure 12 China B and Figure 12 (C). Phototherapy or hydrogel therapy alone can only partially reduce dendritic cell aggregation. In contrast, hydrogel combined with phototherapy reduces CD11c... + The proportion of dendritic cells decreased to 7.77%, close to the level of the healthy group. Furthermore, IMQ significantly increased the expression of CD86, a co-stimulatory molecule associated with dendritic cell maturation and T cell activation. Hydrogel combined with phototherapy significantly reduced the mean fluorescence intensity of CD86, indicating that it can inhibit dendritic cell maturation and antigen-presenting-related activation. Figure 12 (D).

[0089] IMQ treatment leads to CD11b in skin lesions + Ly6G + Neutrophil infiltration was significant, with the proportion of neutrophils increasing from 23.1% in healthy skin to 51.1%. Figure 12 China E and Figure 12 (Middle F). Hydrogel plus phototherapy reduced the neutrophil infiltration rate to 26.4%, while phototherapy and hydrogel alone had weaker effects. Similarly, CD11b after IMQ induction... + F4 / 80 + The proportion of macrophages increases, while hydrogel combined with phototherapy can significantly reduce their proportion. Figure 12 China G and Figure 12 (H). These results suggest that upconversion thermosensitive hydrogels can reduce excessive innate immune cell infiltration in psoriatic lesions.

[0090] Subsequently, the T cell response in the skin was further analyzed. IMQ induction significantly increased CD45. + CD3 + The proportion of T cells indicates enhanced T cell infiltration in the diseased skin. Hydrogel combined with phototherapy significantly reduced CD3+. + T cell aggregation ( Figure 12 I and Figure 13 Flow cytometry was used to further analyze Foxp3-related T cell responses. IMQ treatment increased CD3... + CD4 + Foxp3 signaling in T cells may reflect compensatory or inflammation-related regulatory T cell responses in inflamed skin. Hydrogel plus phototherapy reduced the mean fluorescence intensity of Foxp3 to near-normal levels. Figure 12 (J), suggesting that this treatment may restore abnormal T-cell immune activation to normal rather than causing widespread systemic immunosuppression.

[0091] (2) Immunohistochemical staining verification Immunohistochemical staining further supported the flow cytometry results. CD103 is typically associated with resident memory T cells in skin tissue. CD103 staining was enhanced in IMQ-induced lesions, but significantly decreased after hydrogel + phototherapy. Figure 14 Furthermore, TNF-α and IL-17 staining was significantly enhanced in IMQ-induced psoriatic lesions, while their expression decreased after hydrogel + phototherapy. Figure 15 and 16 These results indicate that upconversion thermosensitive hydrogels can inhibit the production of local inflammatory cytokines and reduce the retention of pathogenic immune cells in the lesion skin.

[0092] (3) Analysis of spleen T cell subsets Because psoriatic inflammation is accompanied by systemic immune activation, splenic T cell subsets were further evaluated. Flow cytometry results showed that CD3+ T cells in the spleen of IMQ-treated mice... + CD4 + and CD3 + CD8 + The proportion of T cells increased ( Figure 12 K and Figure 12 L and Figure 17 , 18 Hydrogel combined with phototherapy significantly reduced CD4 levels. + and CD8 + The proportion of T cells was brought close to healthy levels. These results are consistent with the previously observed reduction in splenomegaly, suggesting that local hydrogel combined with phototherapy can attenuate psoriasis-like inflammation-related systemic immune activation.

[0093] (4) Serum cytokine detection (ELISA) Whole blood from mice was centrifuged at 4°C and 3000 rpm for 10 min, and serum samples were collected. The levels of IL-17A and IL-23 in serum were detected using a mouse IL-17A and IL-23 ELISA kit, following the manufacturer's instructions. Samples were added to microplates pre-coated with antibodies and incubated for 2 h. After washing, biotinylated detection antibodies were added and incubated for 1 h, followed by the addition of streptavidin-HRP conjugate and incubation for 30 min. A TMB substrate solution was added for colorimetric reaction, and the reaction was terminated using a stop solution. The absorbance at 450 nm was measured using a microplate reader.

[0094] IMQ significantly increased the levels of circulating IL-17A and IL-23, two key mediators of the IL-23 / IL-17 axis in psoriasis-causing psoriasis. Figure 12 M and Figure 12 (N). Hydrogel combined with phototherapy significantly reduced serum IL-17A and IL-23 levels, while phototherapy or hydrogel therapy alone had weaker effects. These results further indicate that upconversion thermosensitive hydrogels can inhibit psoriasis-related inflammatory signaling at both local and systemic levels.

[0095] In summary, hydrogel combined with phototherapy remodels the immune microenvironment of IMQ-induced psoriatic lesions by reducing dendritic cell aggregation and maturation, inhibiting neutrophil and macrophage infiltration, decreasing T cell aggregation, attenuating tissue-resident memory T cell and inflammatory cytokine signaling, and restoring splenic T cell overactivation to normal. These immunomodulatory effects provide a mechanistic explanation for the clinical and histological improvements induced by visible light-activated upconversion thermosensitive hydrogels.

[0096] Experiment 4 Transcriptome Analysis To elucidate the molecular mechanism of visible light-activated upconversion thermosensitive hydrogel in treating psoriasis, transcriptomic analysis of mouse dorsal skin tissue was performed using RNA sequencing.

[0097] Total RNA was extracted using TRIzol reagent, and after passing quality testing, sequencing libraries were constructed. Transcriptome sequencing was performed using the Illumina sequencing platform. Principal component analysis (PCA) showed that the hydrogel + phototherapy group samples were significantly separated from the IMQ model group, suggesting that this treatment significantly remodeled the transcriptome characteristics of psoriatic lesions. Figure 19 (A). Under the screening criteria of q-value < 0.05 and |log2FC| > 1, a total of 1659 differentially expressed genes were identified in the hydrogel + phototherapy group compared with the IMQ group. Among them, 797 genes were upregulated and 862 genes were downregulated after hydrogel + phototherapy. Figure 19 (B)

[0098] Functional enrichment analysis revealed that downregulated genes were significantly enriched in biological processes such as cell cycle, cell division, DNA replication, chromosome segregation, mitotic spindle tissue organization, intermediate filament organization, and keratinization after hydrogel + phototherapy. KEGG pathway analysis further indicated that downregulated genes were mainly enriched in pathways involving cell cycle, DNA replication, p53 signaling, motor proteins, cellular senescence, homologous recombination, base excision repair, and mismatch repair. WikiPathways analysis similarly showed that downregulated pathways were mainly enriched in G1 to S phase cell cycle regulation, mismatch repair, p53 signaling, Hedgehog signaling, Wnt signaling, and the integrated IL-17A signaling pathway. These results suggest that hydrogel + phototherapy inhibits transcriptional programs associated with excessive keratinocyte proliferation, mitotic activity, DNA replication, abnormal epidermal differentiation, and psoriasis-related inflammatory signals.

[0099] WikiPathways enrichment analysis of upregulated genes showed significant enrichment in PPAR signaling pathway, retinol metabolism, tryptophan metabolism, glycolysis and gluconeogenesis, matrix metalloproteinases, macrophage markers, iron homeostasis, and lipid-related metabolic pathways, suggesting that hydrogel + phototherapy may promote metabolic remodeling, tissue repair, and inflammation resolution in psoriatic lesions.

[0100] Gene set enrichment analysis (GSEA) further supported the above results. Compared with the IMQ group, the cell cycle pathway (NES=-2.58, p<0.001, FDR<0.001) and DNA replication pathway (NES=-2.49, p<0.001, FDR<0.001) in the hydrogel + light group showed significant negative enrichment. Figure 19 C and Figure 19 The results showed that treatment inhibited the proliferative program driving epidermal thickening in psoriatic arthritis. The PPAR signaling pathway was positively enriched (NES=1.74, p<0.001, FDR=0.029). Figure 19 The presence of E in the middle layer suggests that lipid metabolism and skin barrier repair pathways are activated. The set of genes related to IL-17A signaling also shows a negative enrichment trend. Figure 19 The decrease in T cell infiltration observed by flow cytometry (F) is consistent with the reduced T cell infiltration observed in the middle F.

[0101] The aforementioned transcriptomic changes are consistent with the observed decrease in epidermal thickness, reduction in Ki67 expression, less inflammatory cell infiltration, and weakened IL-23 / IL-17A signaling, providing molecular-level evidence for the therapeutic effect of visible light-activated upconversion thermosensitive hydrogels.

[0102] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The application of a visible light-activated upconversion thermosensitive hydrogel in the preparation of drugs for treating psoriasis, characterized in that, The visible light-activated upconversion thermosensitive hydrogel was prepared using the following method: (1) Preparation of Pr 3+ Y2SiO5 nanoparticles, for the Pr 3+ Y2SiO5 nanoparticles were modified with amino groups. (2) The amino-modified Pr 3+ Y₂SiO₅ nanoparticles were dispersed in water and heated to 90-110℃. An aqueous solution of silver nitrate and KH-550 was added, and the mixture was stirred. Then, trisodium citrate solution was added dropwise. The precipitate was collected, washed, and dried to obtain Ag@Pr 3+ Y2SiO5 upconversion material; (3) Quaternized chitosan, β-glycerol phosphate and hydroxyethyl cellulose were mixed under ice bath conditions to obtain a thermosensitive hydrogel precursor solution; the Ag@Pr obtained in step (2) was then mixed with the quaternized chitosan, β-glycerol phosphate and hydroxyethyl cellulose to obtain a thermosensitive hydrogel precursor solution. 3+ Y2SiO5 upconversion material is dispersed in the thermosensitive hydrogel precursor solution and mixed evenly to obtain the visible light activated upconversion thermosensitive hydrogel.

2. The application according to claim 1, characterized in that, In step (1), Pr 3+ The molar doping amount in Y2SiO5 is 1%-5%.

3. The application according to claim 1, characterized in that, In step (2), the Pr 3+ The molar ratio of Y2SiO5, silver nitrate and trisodium citrate is 0.02:(0.0009-0.0036):(0.0001-0.0026).

4. The application according to claim 1, characterized in that, The mass ratio of the quaternized chitosan, β-glycerol phosphate, and hydroxyethyl cellulose is (0.5-2):2:

1.

5. The application according to claim 1, characterized in that, The Ag@Pr 3+ Y2SiO5 upconversion material emits ultraviolet light with wavelengths of 297-319nm when excited by 450nm visible light.

6. The application according to claim 5, characterized in that, The irradiation time of the visible light is 15-45 minutes.

7. The application according to claim 1, characterized in that, The upconversion thermosensitive hydrogel transforms from a sol state to a gel state at a temperature of 32-37℃.

8. The application according to claim 1, characterized in that, The drug treats psoriasis by inhibiting the IL-23 / IL-17 inflammatory pathway.

9. The application according to claim 1, characterized in that, The drug treats psoriasis by downregulating cell cycle and DNA replication-related pathways.

10. The application according to claim 1, characterized in that, The visible light activated upconversion thermosensitive hydrogel has an upconversion quantum yield of ≥10% under visible light irradiation.

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