A postoperative auxiliary comprehensive treatment system with space-time response and a preparation method and application thereof

Abstract

The application discloses a postoperative auxiliary comprehensive treatment system with spatiotemporal response and a preparation method and application thereof, and relates to the fields of biology and medicine and the technical field of pharmaceutical preparations. The system comprises a temperature-sensitive hydrogel matrix, an anti-inflammatory drug dispersed in the hydrogel matrix, and nanoparticles loaded with an immunomodulator and dispersed in the hydrogel matrix. In an embodiment of the application, a postoperative auxiliary treatment comprehensive system is successfully constructed, and curcumin and MPDA encapsulating R848 are simultaneously loaded in the gel support. The small molecule curcumin is preferentially released from the gel to play an anti-inflammatory role, and R848 needs to be gradually released from the mesopore of the MPDA and the gel, so that the immune microenvironment can be improved after the anti-inflammatory curcumin promotes wound healing.

Description

Technical Field

[0001] This invention relates to the fields of biology and medicine and pharmaceutical formulation technology, specifically to a spatiotemporally responsive postoperative adjuvant comprehensive treatment system and its preparation method and application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance some understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art.

[0003] Surgical resection remains the preferred treatment for solid tumors. However, its long-term efficacy is often limited by the high risk of postoperative recurrence. Although adjuvant therapies such as chemotherapy, radiotherapy, and immunotherapy are currently used clinically to reduce the risk of postoperative recurrence, they have significant limitations. Chemotherapy and radiotherapy may cause systemic toxicity and further suppress immune function, while immune checkpoint inhibitors have limited effectiveness in remodeling the established immunosuppressive tumor microenvironment after surgery. Therefore, developing new treatment regimens to effectively suppress postoperative tumor recurrence has become a critical clinical challenge that urgently needs to be addressed.

[0004] Focusing on the mechanisms of postoperative recurrence, the invasiveness of solid tumors often leads to indistinct tissue boundaries, making complete surgical resection extremely difficult and leaving small residual lesions. Furthermore, the inflammatory response triggered by surgical trauma promotes recurrence and increases the risk of infection by recruiting immunosuppressive cells and hindering wound healing. Specifically, in the early postoperative stage, the inflammatory response promotes the abnormal recruitment of M2 tumor-associated macrophages (M2 TAMs) to the tumor site through pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). These M2 TAMs promote tumor recurrence by secreting immunosuppressive cytokines and promoting the accumulation of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). These factors collectively create a tumor-friendly and immunosuppressive microenvironment. The residual tumor tissue continues to proliferate malignantly and tames the immune cells in the tumor microenvironment to maintain an immunosuppressive phenotype, thereby promoting tumor recurrence. Summary of the Invention

[0005] To address these challenges, this invention proposes an innovative postoperative support system designed for precise spatiotemporal control during the perioperative period. This method integrates inflammation suppression with the controlled clearance of tumor cells, simultaneously accelerating wound healing, reversing the immune microenvironment, and eliminating residual tumor cells. By intervening during this critical window, the strategy of this invention provides a promising new solution for preventing postoperative recurrence and improving patient prognosis.

[0006] The technical solution adopted in this invention is as follows:

[0007] In a first aspect of the invention, a spatiotemporally responsive drug delivery system for preventing postoperative recurrence of solid tumors is provided, the system comprising:

[0008] Thermosensitive hydrogel matrix;

[0009] Anti-inflammatory drugs dispersed in the hydrogel matrix; and

[0010] Nanoparticles loaded with immunomodulators are dispersed in the hydrogel matrix.

[0011] The anti-inflammatory drug is configured to be preferentially released from the hydrogel matrix to suppress inflammation and promote wound healing in the early postoperative period; the nanoparticles loaded with immunomodulators are configured to release the immunomodulators in response to external stimuli and produce a therapeutic effect to clear residual tumor cells and / or reverse the immunosuppressive microenvironment.

[0012] In one or more embodiments of the present invention, the thermosensitive hydrogel matrix is ​​in a flowable sol state at 4°C to 25°C, and can be transformed into a non-flowable gel state in 50 seconds at a body temperature of 37°C.

[0013] In one or more embodiments of the present invention, the thermosensitive hydrogel matrix includes, but is not limited to, chitosan modified with poloxamer F127, a combination of poloxamer F127 and poloxamer F68, or a combination of poloxamer F127 and gelatin.

[0014] Furthermore, the chitosan is a low molecular weight chitosan with a molecular weight of 10 kDa - 50 kDa;

[0015] The preparation of poloxamer F127-modified chitosan in this invention is a conventional prior art that can be obtained by those skilled in the art. For example, Pluronic F127 is first subjected to monocarboxylation to obtain Pluronic F127-COOH, and then combined with low molecular weight chitosan through an amide reaction to obtain a hydrogel material (chitosan-F127).

[0016] In one or more embodiments of the present invention, the anti-inflammatory drug includes, but is not limited to, curcumin or its pharmaceutically acceptable salts, esters or derivatives or other anti-inflammatory small molecule drugs.

[0017] In one or more embodiments of the present invention, the nanoparticles are mesoporous polydopamine nanoparticles (MPDA); the mesoporous polydopamine nanoparticles loaded with immunomodulators can respond to near-infrared light irradiation, generate a photothermal effect and release immunomodulators.

[0018] In one or more embodiments of the present invention, the immunomodulator is a Toll-like receptor 7 / 8 (TLR7 / 8) agonist.

[0019] Furthermore, the TLR7 / 8 agonist is R848.

[0020] In one or more embodiments of the present invention, the external stimulus is near-infrared light irradiation.

[0021] In one or more embodiments of the present invention, after surgical resection of a solid tumor, the drug delivery system is applied to the surgical wound; and external stimulation is applied to the wound at a specific postoperative time point; the external stimulation is 808nm near-infrared laser irradiation with a power density of 1.5 W / cm². 2 The irradiation time is 5 minutes.

[0022] In a second aspect of the invention, a method for preparing the drug delivery system described above is provided, the method comprising the following steps:

[0023] 1) Preparation of nanoparticles loaded with immunomodulators;

[0024] 2) The anti-inflammatory drug is mixed with the immunomodulator-loaded nanoparticles obtained in step 1) to obtain a drug mixture;

[0025] 3) Mix the drug mixture obtained in step 2) with the material solution constituting the thermosensitive hydrogel matrix to obtain a homogeneous pregel solution.

[0026] In one or more embodiments of the present invention, step 1) involves the preparation of the nanoparticles loaded with the immunomodulator, comprising:

[0027] (1) Preparation of MPDA: 1,3,5-trimethylbenzene (TMB) and poloxamer F127 were dissolved in a mixed solution of ethanol and water, Tris buffer and dopamine hydrochloride were added, the mixture was stirred and polymerized, and after centrifugation, washing and drying, MPDA powder was obtained.

[0028] (2) Loading immunomodulator: MPDA and immunomodulator R848 are mixed in a set mass ratio (preferably (1~4): (2~1)), ultrasonically treated, centrifuged to remove unencapsulated R848, and resuspended to obtain R848@MPDA.

[0029] In one or more embodiments of the present invention, in step 2), the mass ratio of the anti-inflammatory drug to the nanoparticles loaded with the immunomodulator is (1~10):(1~20).

[0030] In one or more embodiments of the present invention, in step 2), the concentration of the anti-inflammatory drug is 5-15 μg / mL.

[0031] In one or more embodiments of the present invention, in step 3), the hydrogel matrix material is F127-modified low molecular weight chitosan, and its concentration in the pregel solution is 30~50 mg / mL.

[0032] In a third aspect of the invention, the use of the drug delivery system in the preparation of a medicament for the prevention or treatment of postoperative recurrence of solid tumors is provided.

[0033] In one or more embodiments of the present invention, the solid tumor includes, but is not limited to, lung cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, prostate cancer, sarcoma, brain tumor, etc.

[0034] In one or more embodiments of the present invention, the drug works by means of:

[0035] (i) In the early postoperative period, anti-inflammatory drugs are preferentially released to inhibit the secretion of inflammatory factors and promote wound healing;

[0036] (ii) Nanoparticles are activated by external stimulation to generate a photothermal effect to kill residual tumor cells and induce immunogenic cell death;

[0037] (iii) Release immunomodulators to polarize tumor-associated macrophages from M2 to M1, reversing the immunosuppressive microenvironment.

[0038] The key point of this invention is to address the risk of high recurrence after surgery by developing a comprehensive adjuvant therapy system that can be applied in the perioperative period after surgery. This system integrates early postoperative wound healing, precise and controllable killing of tumor cells, reshaping of the immunosuppressive microenvironment, and construction of immune memory to achieve comprehensive postoperative treatment.

[0039] Compared with the related technologies known to the inventors, one of the technical solutions of the present invention has the following beneficial effects:

[0040] (1) This invention successfully constructed a comprehensive postoperative adjuvant therapy system, which simultaneously loaded the small molecule drug curcumin and MPDA encapsulating R848 into a gel scaffold. The small molecule curcumin preferentially releases from the gel to exert an anti-inflammatory effect, while R848 needs to be gradually released from the mesopores of MPDA and the gel, which can improve the immune microenvironment after curcumin promotes wound healing through anti-inflammatory effects.

[0041] (2) The present invention significantly improves the inflammatory response and reduces the release of inflammatory cytokines; in addition, R848@MPDA can precisely kill tumor cells under laser irradiation, activate the immune response, polarize the macrophage phenotype, improve the immune microenvironment, enhance the anti-tumor effect and enhance the immune memory.

[0042] (3) The preparation method of MPDA, the concentration of the gel scaffold, and the concentration of curcumin in this invention are all optimized data, and their therapeutic effects are good. The raw materials used in this invention are simple, safe, and reliable. The carrier materials are all safe, non-toxic, and biodegradable substances with good biocompatibility. Attached Figure Description

[0043] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0044] Figure 1 (A) Preparation process of MPDA, (B) Electron micrograph of MPDA, (C) Elemental analysis of MPDA.

[0045] Figure 2 Scanning electron microscope images of blank gel and postoperative thermosensitive gel system and evaluation of thermosensitivity.

[0046] Figure 3 Release of Cur and MPDA in Cur+R848@MPDA-gel.

[0047] Figure 4 (A) The amount of IL-6 secreted by macrophages induced by different concentrations of LPS, (B) The secretion of inflammatory cytokines IL-6, IL-12 and IL-1β by macrophages induced by curcumin (Cur) and LPS.

[0048] Figure 5 (A) Temperature rise curves of R848@MPDA after four laser irradiation cycles, (B) Post-laser cytotoxicity of different concentrations of R848@MPDA, (C) Expression of CRT in cells under laser irradiation conditions of R848@MPDA.

[0049] Figure 6 Evaluation of R848 polarized macrophage phenotype in R848@MPDA.

[0050] Figure 7 Evaluation of the antitumor efficacy of Cur+R848@MPDA-gel. Detailed Implementation

[0051] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0052] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, and / or combinations thereof.

[0053] As mentioned in the background section, surgical treatment is the preferred option recommended by clinical guidelines for solid tumors. However, it carries a high risk of recurrence postoperatively. Existing adjuvant strategies are limited by systemic toxicity, insufficient immunomodulation, and poor targeting of the tumor microenvironment, resulting in unsatisfactory treatment outcomes. Therefore, this invention develops a novel spatiotemporally responsive postoperative adjuvant comprehensive treatment system that integrates wound repair, immunomodulation, and precise tumor ablation to promote postoperative recovery and prevent infection and recurrence.

[0054] To construct a comprehensive postoperative adjuvant therapy system, this invention develops a temperature-sensitive gel system that enables spatiotemporal control of wound healing, immune modulation, and targeted tumor cell clearance during the postoperative period. In one specific embodiment of this invention, this multifunctional platform integrates curcumin and mesoporous dopamine nanoparticles (MPDA) loaded with the TLR7 / 8 agonist R848, reversing the immunosuppressive microenvironment and preventing tumor recurrence through a cascade strategy. The gel scaffold is composed of F127-modified low-molecular-weight chitosan and can be directly applied to the surgical site immediately after tumor resection. Its thermosensitivity and adhesiveness ensure stable retention on the wound surface. Furthermore, this invention is not limited to the gel mentioned herein; any gel possessing thermosensitivity, adhesiveness, and safety can be used. In the early postoperative stage, curcumin is preferentially released, effectively inhibiting the inflammatory response, accelerating wound healing, and suppressing the migration of M2 tumor-associated macrophages (TAMs). This early intervention alleviates local immunosuppression, preparing the microenvironment for subsequent treatment. As time progresses postoperatively, the system can provide responsive therapy to emerging tumor regeneration. Local irradiation with an 808 nm laser activates the photothermal properties of MPDA, enabling precise ablation of residual tumor cells and simultaneously releasing damage-associated molecular patterns to initiate a T-cell-mediated immune response. Simultaneously, the release of R848 repolarizes M2 tumor-associated macrophages into anti-tumor M1 macrophages, further reversing immunosuppression and enhancing anti-tumor immunity, providing a new strategy and approach for postoperative treatment.

[0055] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0056] Example

[0057] To construct a comprehensive postoperative adjuvant therapy system, a thermosensitive hydrogel matrix was designed to load curcumin and MPDA (R848@MPDA) loaded with the TLR7 / 8 agonist R848. The thermosensitive hydrogel matrix was prepared by cross-linking monocarboxyl-modified F127 and low molecular weight chitosan via an amide reaction. MPDA, polymerized from dopamine molecules, has a mesoporous structure that ensures efficient loading of R848. Subsequently, curcumin and R848@MPDA were co-loaded into the thermosensitive hydrogel matrix material. Following administration, small-molecule curcumin is preferentially released, alleviating early postoperative inflammatory responses and inhibiting the migration of immunosuppressive cells, thus easing the immunosuppressive microenvironment and reducing tumor growth. However, over time, the tumor adapts to its surrounding environment, promoting its own growth. R848@MPDA enables controlled tumor clearance under laser irradiation, activating immune responses and immune memory. Simultaneously, R848 can repolarize M2 tumor-associated macrophages into anti-tumor M1 macrophages, creating a suitable tumor microenvironment for immune response and improving postoperative anti-recurrence efficacy. The preparation process and characterization are shown below:

[0058] 1.1 Preparation and Characterization of R848@MPDA

[0059] First, the MPDA was prepared. 0.36 g TMB and 0.36 g F127 were dissolved in a mixture of 60 mL ethanol and 65 mL double-distilled water. Then, 90 mg Tris and 60 mg dopamine hydrochloride were dissolved in 10 mL double-distilled water and added to the above mixture. The mixture was stirred at room temperature for 24 h. After centrifugation, the mixture was washed three times each with alternating ethanol and double-distilled water, and then lyophilized to obtain MPDA powder.

[0060] Two solutions of MPDA and R848 (mass ratio 2:1) were mixed, sonicated for 1 h, and allowed to stand for 30 min. The solution was then centrifuged at 8000 rpm for 10 min. The supernatant was discarded to remove unencapsulated R848, and the precipitate was resuspended and mixed to obtain R848@MPDA. The morphology of HAM was characterized by transmission electron microscopy, and elemental analysis was performed. Figure 1 This demonstrates the successful preparation of R848@MPDA.

[0061] 1.2 Preparation and characterization of the postoperative thermosensitive gel system

[0062] F127-modified low molecular weight chitosan: First, Pluronic F127 was monocarboxylated to obtain Pluronic F127-COOH, which was then combined with low molecular weight chitosan via an amide reaction to prepare a hydrogel material (chitosan-F127). The specific steps are as follows: 0.24 mmol Pluronic F127, 0.37 mmol succinic anhydride, and 0.26 mmol DMAP were dissolved in anhydrous 1,4-dioxane to synthesize Pluronic F127-COOH. Then, 0.26 mmol triethylamine was added and the mixture was stirred continuously for 24 hours. After the reaction was complete, the reaction solution was dialyzed in a 3500 Da dialysis bag for 48 hours, and finally, the product - Pluronic F127-COOH - was obtained by freeze-drying.

[0063] Subsequently, 2.8 g of Pluronic F127-COOH was dissolved in 0.1 M MES buffer containing 116 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 32 mg of N-hydroxysuccinimide (NHS) to prepare a hydrogel material. Separately, 0.7 g of commercially available low molecular weight chitosan (approximately 20 kDa) was dissolved in 0.1 M hydrochloric acid solution, and the pH of the mixture was adjusted to 4.5 with 0.5 M sodium hydroxide. Finally, the Pluronic F127-COOH solution and chitosan solution were mixed and stirred for 24 hours, transferred to a 20000 Da dialysis bag, and dialyzed for 48 hours. The solution in the dialysis bag was collected and freeze-dried for later use.

[0064] F127-modified low molecular weight chitosan was dissolved at a concentration of 40 mg / mL to obtain a blank gel scaffold. F127-modified low molecular weight chitosan (40 mg / mL, 0.5 mL) was dissolved in a mixture of curcumin solution (10 μg / mL, 0.5 mL) and R848@MPDA solution (100 μg / mL, 0.5 mL) to obtain a postoperative thermosensitive gel system (hereinafter referred to as Cur+R848@MPDA-gel). The morphology and pore size were evaluated using scanning electron microscopy, and the results are as follows: Figure 2 As shown, both the blank gel scaffold and the postoperative thermosensitive gel system have micron-sized pores, and R848@MPDA adhesion can be observed in the postoperative thermosensitive gel scaffold system. Meanwhile, the postoperative thermosensitive gel system is fluid at 4°C but gels at 37°C. Figure 2 ).

[0065] 1.3 Spatiotemporal responsiveness release

[0066] Cur+R848@MPDA-gel exhibits temperature-sensitive gelation after drug administration. Subsequently, due to the molecular weight difference between curcumin and R848@MPDA, curcumin is preferentially released from Cur+R848@MPDA-gel. Therefore, the time-response release of Cur and MPDA was evaluated using a Transwell system. Figure 3 As shown, curcumin is rapidly released in the early stages within 11 days to exert a highly effective anti-inflammatory effect, while MPDA is released more slowly, enabling effective tumor suppression after early postoperative anti-inflammatory treatment.

[0067] 1.4 Anti-inflammatory response of curcumin

[0068] A lipopolysaccharide (LPS) inflammatory model was constructed to simulate postoperative inflammatory response, and the anti-inflammatory effect of curcumin was evaluated. First, the successful induction of the LPS model was assessed, such as… Figure 4 As shown in Figure A, macrophage IL-6 secretion increased under different concentrations of LPS stimulation and incubation times, demonstrating the successful induction of the postoperative inflammation model. Subsequently, LPS stimulation was co-incubated with curcumin to evaluate the secretion of inflammatory cytokines by macrophages, such as... Figure 4 As shown in Figure B, the secretion of inflammatory cytokines IL-6, IL-12, and IL-1β was significantly downregulated, demonstrating that curcumin has an anti-inflammatory effect, can achieve early postoperative anti-inflammatory response, and promote wound healing.

[0069] 1.5 Evaluation of the anti-tumor effect and immune activation capacity of R848@MPDA laser

[0070] R848@MPDA (50 μg / mL) was laser-irradiated (808 nm, 1.5 W / cm2, 5 min), then left to stand for 10 min. Temperature changes were recorded every 30 s. This process was repeated for four cycles to evaluate the photothermal stability and heating rate of R848@MPDA. Figure 5 A). Subsequently, different concentrations of R848@MPDA were co-incubated with mouse colorectal cancer cells MC38 to evaluate its ability to kill tumor cells under laser irradiation. The results are as follows: Figure 5 As shown in Figure B, the antitumor effect was better under laser irradiation with increasing R848@MPDA concentration, demonstrating that R848@MPDA can efficiently kill tumor cells. Further evaluation of R848@MPDA's ability to activate T cell immune responses was conducted using calreticulin CRT as an indicator, evaluating the ability of R848@MPDA to stimulate CRT eversion. The results are as follows... Figure 5 As shown in Figure C, the fluorescence images show that the CRT expression in the R848@MPDA+laser group was significantly higher than that in the R848@MPDA and Control groups, demonstrating that R848@MPDA can activate the immune response after laser irradiation.

[0071] 1.6 Evaluation of R848 polarized macrophage phenotype in R848@MPDA

[0072] The ability of R848 to polarize M2 macrophages to the M1 phenotype was evaluated in RAW264.7 cells. Mouse RAW264.7 macrophages were seeded at 1×10⁵ cells per well in 12-well plates. After cell attachment, medium containing 15 ng / mL was added and cultured for 12 h to induce the M2 phenotype, mimicking the abundant M2 macrophage infiltration in the tumor microenvironment. Subsequently, the IL-4-containing medium was replaced with blank medium, R848, and R848@MPDA, and incubated for another 24 h. After incubation, cells from each group were collected, labeled with F4 / 80, CD80, and CD206 antibodies, and macrophage phenotypes were detected by flow cytometry. Results are as follows: Figure 6 As shown, R848 has the ability to polarize M2 macrophages into M1 macrophages. When loaded into MPDA, R848@MPDA also demonstrated the ability to polarize M2 macrophages into M1 macrophages.

[0073] 1.7 In vivo anti-recurrence effect of the postoperative thermosensitive gel system

[0074] A colorectal cancer MC38 model was established in C57BL / 6 mice bearing a tumor in the right axilla. When the tumor grew to approximately 300 mm³, 80% of the tumor was surgically removed, and NS, Blank-gel, Cur-gel, R848@MPDA-gel, and Cur+R848@MPDA-gel were applied to each tumor (5 mice / group). Subsequently, after day 10, laser irradiation was performed every three days (808 nm, 1.5 W / cm², 5 min), and tumor volume was recorded every two days. After 15 days, the mice were euthanized, and tumor tissue was collected. Figure 7 As shown, the results indicate that the Blank-gel and NS groups had similar efficacy, while Cur-gel was able to inhibit tumor growth to some extent. R848@MPDA-gel demonstrated superior efficacy compared to the Cur-gel group under laser irradiation. The Cur+R848@MPDA-gel group exhibited the best anti-tumor efficacy, proving that the designed postoperative thermosensitive gel system provides a new comprehensive treatment model for postoperative care.

[0075] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A spatiotemporally responsive drug delivery system for preventing postoperative recurrence of solid tumors, characterized in that, The system includes: Thermosensitive hydrogel matrix, wherein the thermosensitive hydrogel matrix is ​​chitosan modified with poloxamer F127; An anti-inflammatory drug dispersed in the hydrogel matrix, wherein the anti-inflammatory drug is curcumin or a pharmaceutically acceptable salt thereof; as well as Nanoparticles dispersed in the hydrogel matrix and loaded with an immunomodulator, wherein the nanoparticles are mesoporous polydopamine nanoparticles (MPDA); and the immunomodulator is Toll-like receptor 7 / 8 agonist R848. The anti-inflammatory drug is configured to be preferentially released from the hydrogel matrix to suppress inflammation and promote wound healing in the early postoperative period; the nanoparticles loaded with immunomodulators are configured to release the immunomodulators and generate a photothermal therapeutic effect in response to external stimuli to clear residual tumor cells and / or reverse the immunosuppressive microenvironment; the external stimulus is near-infrared light irradiation.

2. The spatiotemporally responsive drug delivery system for preventing postoperative recurrence of solid tumors as described in claim 1, characterized in that, The chitosan is a low molecular weight chitosan with a molecular weight of 10 kDa - 50 kDa; the thermosensitive hydrogel matrix is ​​in a flowable sol state at 4℃ to 25℃, and can be transformed into a non-flowable gel state in 50s at a body temperature of 37℃.

3. A method for preparing the drug delivery system according to claim 1 or 2, characterized in that, The method includes the following steps: 1) Preparation of nanoparticles loaded with immunomodulators; 2) The anti-inflammatory drug is mixed with the immunomodulator-loaded nanoparticles obtained in step 1) to obtain a drug mixture; 3) Mix the drug mixture obtained in step 2) with the material solution constituting the thermosensitive hydrogel matrix to obtain a homogeneous pregel solution.

4. The preparation method according to claim 3, characterized in that, In step 1), the method for preparing nanoparticles loaded with immunomodulators includes: (1) Preparation of MPDA: 1,3,5-trimethylbenzene and poloxamer F127 were dissolved in a mixed solution of ethanol and water, Tris buffer and dopamine hydrochloride were added, the mixture was stirred and polymerized, and after centrifugation, washing and drying, MPDA powder was obtained. (2) Loading immunomodulator: MPDA and immunomodulator R848 are mixed in a set mass ratio, sonicated, centrifuged to remove unencapsulated R848, and resuspended to obtain R848@MPDA.

5. The preparation method according to claim 3, characterized in that, In step 2), the mass ratio of the anti-inflammatory drug to the nanoparticles loaded with immunomodulators is (1~10):(1~20).

6. The preparation method according to claim 3, characterized in that, In step 3), the hydrogel matrix material is F127-modified low molecular weight chitosan, and its concentration in the pregel solution is 30~50 mg / mL.

7. Use of the drug delivery system of claim 1 or 2 in the preparation of a medicament for the prevention or treatment of postoperative recurrence of solid tumors.

8. The application as described in claim 7, characterized in that, The drug works by means of the following: (i) In the early postoperative period, anti-inflammatory drugs are preferentially released to inhibit the secretion of inflammatory factors and promote wound healing; (ii) Nanoparticles are activated by external stimulation to generate a photothermal effect to kill residual tumor cells and induce immunogenic cell death, wherein the external stimulation is near-infrared light irradiation; (iii) Release immunomodulators to polarize tumor-associated macrophages from M2 to M1, reversing the immunosuppressive microenvironment.

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