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A Mannose-Modified Lipid Calcium Phosphate Nanoparticle Vaccine Increased the Anti-Tumor Immune Response by Modulating the Tumor Microenvironment

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22 March 2024

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22 March 2024

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Abstract
With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as a potential therapeutic strategy. The potential role of the mannose-modified lipid calcium phosphate nanoparticle vaccine in enhancing the anti-tumor immune response was investigated. The aim of this study was to investigate the effect of mannose modification on the immune response of nanoparticles in regulating the tumor microenvironment through systematic review and analysis and to explore its potential clinical application in tumor therapy. Currently, despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and overexpression of immunosuppressive factors limit its clinical application. Therefore, this study will explore how to intervene in the immunosuppressive mechanism in the tumor microenvironment through mannose-modified lipid calcium phosphate nanoparticle vaccines so as to improve the immunotherapy effect of tumor patients and provide new ideas and strategies for the field of tumor therapy.
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Subject: Biology and Life Sciences  -   Biochemistry and Molecular Biology

1. Introduction

In the current medical field, tumor immunotherapy, as a revolutionary treatment, has brought new hope for tumor patients[1,2,3]. However, despite some success, tumor immunotherapy still faces a number of challenges and limitations[4].
The core idea of tumor immunotherapy is to activate the body's own immune system to attack and eliminate tumor cells[5]. However, the presence of the tumor microenvironment seriously affects the activity and function of immune cells, thus weakening the effectiveness of immunotherapy[6,7,8,9,10]. The tumor microenvironment includes tumor cells, immune cells, blood vessels, interstitial cells, and other components, which interact with each other in a complex way, forming a situation of immunosuppression[11]. The overexpression of immunosuppressive factors, the existence of immune escape mechanisms, and the immunosuppressive effect of tumor cells are some of the main challenges facing tumor immunotherapy[12]. To overcome these challenges, in recent years, scientists have focused on finding new strategies and methods to improve the effectiveness of tumor immunotherapy[13,14,15,16]. As a new therapeutic strategy, nanoparticle vaccines have attracted much attention[17]. Compared with traditional vaccines, nanoparticle vaccines have better biological stability, higher drug loading capacity, and stronger targeting, which can effectively improve the effect of immunotherapy[18,19,20].
As a new nanoparticle carrier, the mannose-modified lipid calcium phosphate nanoparticle vaccine has unique advantages and potential application prospects[21,22,23,24,25]. Mannose modification can make it easier for nanoparticles and tumor cells to be recognized and taken up[26]. This can increase the amount of vaccine that is enriched in tumor tissues, which improves the effectiveness of tumor immunotherapy[27,28,29,30]. In addition, mannose modification can also regulate the expression of immunosuppressive factors in the tumor microenvironment, destroy the interaction between tumor cells and immune cells, and further enhance the effect of immunotherapy[31,32,33].
In conclusion, the mannose-modified lipid calcium phosphate nanoparticle vaccine has great potential and broad application prospects as a new type of tumor immunotherapy. In this paper, we will systematically review and analyze the research progress of this vaccine in enhancing the anti-tumor immune response and regulating the tumor microenvironment, so as to provide a theoretical basis and practical guidance for further research in this field.

2. Regulation and Influence of Tumor Microenvironment

2.1. Characteristics of Tumor Microenvironment and Immunosuppressive Mechanism

The tumor microenvironment is an important part of tumor growth and development, and its characteristics are closely related to the immunosuppressive mechanism[34,35,36]. There are a lot of immunosuppressive factors, like transforming growth factor β (TGF-β) and interleukin-10 (IL-10), in the area around the tumor[35]. These can stop immune cells from doing their job and make it harder for them to find and kill tumor cells. A lot of immunosuppressant molecules are made by tumor cells and the cells that surround them, like programmed death ligand-1 (PD-L1), acidic extracellular matrix protein (TSP), and others[36,37,38,39,40]. These molecules work with ligands on the surface of immune cells to make the immune system tolerate and escape. In addition, the highly acidified and hypoxic environment in the tumor microenvironment is also an important factor in immunosuppression, which not only affects the activity and function of immune cells but also induces apoptosis and functional abnormalities in immune cells[41,42,43,44]. The inflammatory response and immune cell infiltration in the tumor microenvironment are also closely related to immunosuppression[45,46,47,48]. The inflammatory response can promote the activation and infiltration of immune cells, but it can also lead to the functional polarization and immune escape of immune cells[49]. The tumor microenvironment provides favorable conditions for tumor escape by regulating the activity, function, and quantity of immune cells and changing the local physiological environment, thereby inhibiting the immune response[50].
The combined application of bio-3D printing technology and bio-nanocarrier technology has constructed a new tumor treatment platform[51,52,53,54]. 3D bioprinting can accurately manufacture complex three-dimensional structures, while bionanocarrier technology can effectively deliver drugs or genes[55]. This combined application platform can enable customized tumor treatment programs, targeting drugs or gene carriers to the tumor site to improve treatment effectiveness[56]. In addition, the combination of these two technologies can improve the tumor immune microenvironment[57,58,59,60]. The tumor immunosuppressive microenvironment can be controlled by releasing nanocarriers carrying specific immunomodulators. It can also boost the activity of immune cells, help tumor cells die and immune cells invade, and improve the immune response of patients[61]. This combined application platform provides a new way for personalized and precise tumor therapy and has important clinical application prospects(Figure 1).

2.1.1. Cell Interaction with Tumor Stroma

Cell interactions in the tumor microenvironment are closely related to tumor mesenchyma and have important effects on the immune response[62,63,64]. The tumor stroma is composed of tumor cells, stromal cells, and stroma, and its complex cellular interactions affect the characteristics of the tumor microenvironment and the mechanism of immunosuppression[65]. Tumor cells influence the behavior of surrounding cells by secreting cytokines and chemokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF), and regulating tumor stromal formation and function[66]. Mesenchymal cells, including tumor-associated macrophages (TAMs) and tumor-associated fibrocytes (CAFs), interact with tumor cells by secreting cytokines and molecules, such as TGF-β and IL-6, to promote tumor growth, invasion, and metastasis and inhibit the activity of immune cells[67,68,69,70].
The pharmacokinetic study of carrying antitumor drugs with nanoparticles as carriers has shown remarkable effects[71]. In a mouse tumor-forming model, the nanocarrier can effectively improve the bioavailability and stability of the drug in vivo, thereby prolonging the plasma half-life of the drug and enhancing the sustained release effect of the drug in vivo[72]. At the same time, in terms of brain metastases, this nanoparticle shows excellent ability to penetrate meninges and target tumors, so that anti-tumor drugs can effectively cross the blood-brain barrier to reach brain tumor foci and then exert anti-tumor effects(Figure 2).

2.1.2. Immune Escape and Tumor Suppressor Cells

Immune escape and tumor suppressor cells in the tumor microenvironment are important reasons for the hindered immune response[73,74,75]. Tumor cells and their surrounding cells and molecules work together in the tumor microenvironment to form a pattern of immune escape[76]. Tumor cells make too many immunosuppressive molecules, like PD-L1 and PD-L2, and immunosuppressive factors, like TGF-β and IL-10. These stop immune cells from working and make it harder for them to find and kill tumor cells[77]. To add to this, tumor suppressor cells in the area around the tumor, like TAMs and Tregs, control the immune response and help the tumor grow and spread by releasing immunosuppressive substances like IL-10 and TGF-β[78,79,80].
The photoacoustic imaging process of the mannose-modified lipid calcium phosphate nanoparticle vaccine in tumor mouse models(Such as Hepatocellular carcinoma, HCC) consists of the following steps: Related study establish the mouse tumor model by selecting suitable cancer cell lines. The mannose-modified lipid calcium phosphate nanoparticle vaccine was injected into mice to evaluate its effect on regulating the tumor microenvironment. Next, the study used ultrasound imaging technology to image the tumors in the mice, observing the vaccine's distribution and the state of tumor growth[81]. In imaging data processing, photoacoustic signals need to be unmixed and oxygen saturation (StO2) calculated to assess the oxygenation level of tumor tissue. Additionally, we must stain the tumor tissue to identify angiogenesis, hypoxia, and molecular markers linked to tumor immune escape[82]. Through this process, the anti-tumor immune effect of the mannose-modified lipid calcium phosphate nanoparticle vaccine in mice can be comprehensively evaluated, which provides an important reference for further clinical research(Figure 3).

2.2. Role of Nanoparticles in the Immune System

2.2.1. Structure and Function of Lipid Calcium Phosphate Nanoparticles

Lipid calcium phosphate nanoparticles are important nanocarriers that have the potential to modulate anti-tumor immune responses in the immune system[83]. These nanoparticles are structurally designed to improve vaccine stability, biocompatibility, and immunogenicity.The core of the lipid calcium phosphate nanoparticles is a kernel composed of calcium phosphate that can stably coat vaccine antigens[84]. Its surface is often modified with molecules such as mannose, which are used to enhance the specific recognition of antigens and promote antigen presentation and uptake by immune cells[85]. Moreover, the lipid envelope of nanoparticles can improve the stability of the vaccine, prolong its circulation time in the body, and enhance the targeted delivery of immune cells[86]. These lipid calcium phosphate nanoparticles can interact with antigen-presenting cells in the immune system to help process and present antigens more effectively. This makes T cells and B cells respond more strongly. The nanoparticles can also mimic the structure and appearance of the virus. This makes the immune system react strongly, which improves the body's ability to find and destroy tumor cells[87]. In general, as an effective vaccine carrier, lipid calcium phosphate nanoparticles play an important role in the immune system, enhancing the anti-tumor immune response by promoting antigen presentation and immune cell activation, and providing new strategies and hopes for tumor treatment.
Our study can use photoacoustic imaging (PA) to measure oxidative stress in lipid calcium phosphate nanoparticles. Lipid calcium phosphate nanoparticles were injected into the tumor site to locate the targeted organs and tumor sites in vivo, and the distribution and signal intensity of lipid calcium phosphate nanoparticles were monitored in real time by photoacoustic imaging technology, and the intensity of the PA signal reflected the degree of oxidative stress[88]. During the observation process, we can infer the degree of oxidative stress in the tumor microenvironment from the changes in signal intensity, and further evaluate the role of lipid calcium phosphate nanoparticles in modulating the tumor immune response[89]. This process effectively combines lipid calcium phosphate, nanoparticle technology, and photoacoustic imaging technology to provide a feasible, non-invasive measurement method for the study of oxidative stress in the tumor microenvironment and provides an important reference for the optimal design of anti-tumor immunotherapy(Figure 4).

2.2.2. Immune System Interaction with Nanoparticles

The role of nanoparticles in the immune system is an important research area, and their interaction with the immune system has an important impact on the anti-tumor immune response[90,91,92,93,94]. Nanoparticles can act as effective carriers for vaccines, delivering antigens stably to the immune system. By changing their surface in the right way, nanoparticles can better recognize antigens and deliver them to immune cells more precisely, which helps activate immune cells and present antigens[95]. The size, shape, and surface properties of nanoparticles can regulate their absorption, distribution, and metabolism in the immune system, affecting their recognition and response to immune cells[96]. In particular, the specific structural design of nanoparticles can mimic the characteristics of pathogens, inducing the immune system to produce a specific and persistent immune response[97]. Nanoparticles can also regulate the immunomodulatory role of the immune system by stimulating the activity of immune cells and secreting immunomodulatory factors, enhancing the immune response[98]. The tumor MRNA-LNPS vaccine uses nucleic acid nanocarrier technology to deliver mRNA encoding tumor-associated antigens to body cells, prompting the synthesis of corresponding antigen proteins in cells, thus triggering specific immune responses[99]. The interaction mechanism between the vaccine and the immune system mainly includes two aspects: one is to promote antigen expression through the imported mRNA, activate antigen-presenting cells, and initiate the autoimmune response; the second is to stimulate the body's natural immune response by simulating virus infection[100]. These mechanisms are similar to the action principle of the COVID-19 nucleic acid vaccine, which stimulates the immune system to produce targeted antibodies and cellular immune responses through the antigen encoded by nucleic acid. In addition, the association between the tumor mRNA-LNPs vaccine and tumor immunity lies in the fact that by inducing immune cells to recognize and attack tumor cells, the tumor microenvironment is changed, thus enhancing the anti-tumor immune response[101,102,103,104]. The mechanism of this vaccine is similar to that of the COVID-19 vaccine, but it targets tumor antigens, which is expected to bring new breakthroughs in tumor immunotherapy(Figure 5).

3. Design and Preparation of Mannose Modified Lipid Calcium Phosphate Nanoparticle Vaccine

3.1. Techniques and Principles of Mannose Modification

The design and preparation of mannose-modified lipid calcium phosphate nanoparticle vaccine is a critical and complex process, and its successful realization depends on various techniques and principles[105]. Mannose modification technology is to chemically covalently bind mannose to the surface of lipid calcium phosphate nanoparticles to endow vaccine with good biocompatibility and stability[106]. The core of this step is to control the modification reaction conditions to ensure adequate modification of mannose and avoid the occurrence of side reactions[107,108,109]. The preparation of lipid calcium phosphate nanoparticles is based on the principle of nanotechnology, and the raw materials such as lipid calcium phosphate are prepared into nanoparticles with a certain size and shape by a suitable method. The key to this step is the selection of appropriate materials and process parameters, as well as characterization and optimization of the properties of the nanoparticles[110]. A comprehensive consideration of mannose modification technology and nanoparticle preparation principle can achieve accurate design and effective preparation of lipid calcium phosphate nanoparticle vaccine, providing a reliable experimental basis for subsequent anti-tumor immune response research.

3.1.1. Mannose Modification and Immune Response

The design and preparation of a mannose-modified lipid calcium phosphate nanoparticle vaccine is a key research task. Using mannose modification technology, mannose can be added to the surface of nanoparticles to make them more biocompatible and stable in living cells. They may also be able to change the immune system[111,112,113,114]. This modification can change the surface charge and structure of the nanoparticles, thus affecting the recognition and response of immune cells. Furthermore, mannose-modified nanoparticles can regulate the tumor microenvironment through immune induction against tumor-associated antigens and promote the occurrence and enhancement of anti-tumor immune responses[115]. Therefore, this design and preparation process not only considers the stability and biocompatibility of the vaccine but also integrates the strategy of immune regulation, providing a new idea and method for enhancing the anti-tumor immune response[116,117,118]. Mannose is a kind of natural polysaccharide. In the process of purification, acid hydrolysis, alkali precipitation, and gel filtration are often used to obtain high-purity mannose[119]. In terms of biotransformation, microbial fermentation techniques, such as Escherichia coli or yeast, are usually used to introduce target genes into the host through genetic engineering methods to synthesize mannose[120]. Mannose modification technology is used to covalently connect mannose to the surface of lipid calcium phosphate nanoparticles, which is often achieved by chemical crosslinking or enzyme catalysis. The development of these technologies has provided researchers with effective means to improve the biological activity and drug delivery performance of nanoparticles, thus playing an important role in tumor immunity vaccine research(Figure 6).

3.1.2. Effect of Mannose Modification on Vaccines

Mannose modification can confer good biocompatibility and immunological activity on nanoparticle vaccines[121]. Mannose modification can improve the stability of the vaccine and increase its circulation time in the body. In addition, mannose-modified nanoparticles can bind specifically to immune cells to improve the cellular uptake rate and antigen delivery efficiency of the vaccine[122,123,124]. Mannose modification can also turn on certain immune signaling pathways and improve the ability of antigen-presenting cells to show antigens, which makes the immune response of antigen-specific T cells stronger[125,126,127,128]. In the design and preparation of the mannose-modified lipid calcium phosphate nanoparticle vaccine, the influence of mannose modification on the vaccine is reflected in the aspects of improving stability, enhancing immune activity, and promoting antigen presentation, which provides strong technical support for tumor immunotherapy[129].
Mannose-modified lipid calcium phosphate nanoparticles have demonstrated a potentially revolutionary role in cancer therapy, and their ability to target cancer-causing long non-coding Rnas has brought new hope for cancer therapy[130]. By regulating the tumor microenvironment, the nanoparticles can not only inhibit the growth and spread of tumor cells but also enhance the body's anti-tumor immune response[131]. At the same time, combined with the research progress on tumor immunity, mannose-modified lipid calcium phosphate nanoparticles are not only a means of direct attack against tumor cells but also an innovative strategy to promote the body's immune system to participate in the anti-tumor process(Figure 7).

3.2. Design and Preparation of Lipid Calcium Phosphate Nanoparticles

3.2.1. Preparation Method and Structural Advantages

Lipid calcium phosphate (CaP) nanoparticles have attracted much attention due to their unique advantages in vaccine delivery systems. Its design and preparation are essential for improving the bioavailability and immunological efficacy of vaccines[132,133,134,135]. Usually, the preparation process includes the solvent precipitation method and the co-precipitation method[136]. In solvent precipitation, the addition of phosphate and calcium ions causes the formation of calcium phosphate nanoparticles in solution. The co-precipitation of the drug and calcium phosphate is typically how the co-precipitation method produces the drug's carrier[137,138,139,140]. In addition, mannose-modified lipid calcium phosphate nanoparticles have attracted much attention in recent years[141]. The preparation methods include pre-modification synthesis and post-modification synthesis. In pre-modification synthesis, the mannose group reacts with calcium phosphate nanoparticles at the same time to form mannose-modified nanoparticles[142,143,144,145]. In post-modification synthesis, calcium phosphate nanoparticles are first synthesized and then chemically or physically bound to mannose groups[146]. The mannose modification makes the nanoparticles more biocompatible and helps them target better, which makes the vaccine more effective at delivering antigens in living organisms[147,148,149,150]. The design and preparation of lipid calcium phosphate nanoparticles is the key link in the research. Their structural advantages provide a good platform for vaccine delivery and lay the foundation for regulating the tumor microenvironment and enhancing the anti-tumor immune response.

3.2.2. Stability and Biocompatibility of Nanoparticles

Lipid calcium phosphate (CaP) nanoparticles are an important vaccine delivery system and have potential applications in anti-tumor immunotherapy[151]. Their design and preparation need to take into account the stability and biocompatibility of nanoparticles, which are essential to improving vaccine effectiveness and safety[152,153,154]. The stability of nanoparticles can be achieved by adjusting preparation methods and adding surface modifiers. In the preparation process, the size, morphology, and dispersion of nanoparticles can be controlled by solvent precipitation or the co-precipitation method to ensure their stability[155]. Also, using the right surface modifiers, like polyvinylpyrrolidone (PVP), can make nanoparticles more stable and stop them from being cleared out of the bloodstream and breaking down in living things[156].
Biocompatibility is one of the important indicators to evaluate the application of nanoparticles[157]. Mannose-modified lipid calcium phosphate nanoparticles have received much attention due to their good biocompatibility[158]. Mannose, as a kind of natural sugar in the human body, has good biocompatibility and biodegradability, which can reduce the immune response and toxic side effects on the body[159]. Mannose-modified nanoparticles can effectively avoid the clearance and decomposition of nanoparticles caused by immune responses, thus extending their circulation time in the body and increasing their accumulation in tumor tissues[160]. Additionally, changing the mannose can improve the specific binding between nanoparticles and tumor cells, allowing for more precise targeted delivery and a better immune response against the tumor in the vaccine[161,162,163,164,165].
In general, the stability and biocompatibility of lipid calcium phosphate nanoparticles are the problems that need to be paid attention to and solved in the research. Through rational design and preparation methods and the introduction of biocompatible modifications such as mannose, the application effect of nanoparticles in anti-tumor immunotherapy can be effectively improved, providing strong support for regulating the tumor microenvironment and enhancing the anti-tumor immune response.

4. Immunomodulatory Mechanism of Mannose Modified Lipid Calcium Phosphate Nanoparticle Vaccine

4.1. Tumor Antigen Presentation and T Cell Activation

4.1.1.

The mannose-modified lipid calcium phosphate nanoparticle vaccine plays an important role in enhancing the anti-tumor immune response, and its immune regulation mechanism involves several links[166]. As a carrier, this nanoparticle can effectively load tumor antigens and their related immune stimulators (such as proteins, nucleic acids, etc.) stably on its surface or inside. Mannose-modified nanoparticles can achieve precise, targeted delivery through specific binding to tumor cell surfaces[167,168,169,170]. This targeted loading allows the nanoparticles to be more efficiently sought out in tumor tissue and swallowed by tumor cells[171]. Nanoparticles release tumor antigens that are loaded on them. This makes it easier for antigen-presenting cells, like dendritic cells, to take in and process these antigens, which then causes immune cells to recognize and respond to the tumor antigens. In addition, mannose modification is able to interact with specific receptors on the surface of tumor cells to promote intracellular phagocytosis and the internal presentation of nanoparticles[172,173,174,175,176,177,178,179,180]. Finally, the release of these immune stimulators and the presentation of tumor antigens will activate the body's immune system, especially promoting the activation and proliferation of antigen-specific T cells and B cells, thus strengthening the immune response to tumors[181,182,183,184].
The mannose-modified lipid calcium phosphate nanoparticle vaccine regulates the tumor microenvironment and enhances the anti-tumor immune response by targeting tumor antigen delivery, promoting antigen presentation, activating immune cells, and providing new ideas and methods for tumor therapy.

4.1.2. Activation of T Cells by Mannose Modified Lipid Calcium Phosphate Nanoparticle Vaccine

The mannose-modified lipid calcium phosphate nanoparticle vaccine changes the microenvironment of the tumor, which boosts the immune response against it[185]. One way it does this is by activating T cells, T cells are an important part of the immune system and play a key role in recognizing and eliminating tumor cells[186,187,188]. Mannose-modified nanoparticles can enhance the immune response by promoting the activation and proliferation of T cells in a variety of ways[189].
Mannose-modified nanoparticles can effectively improve the delivery efficiency of tumor antigen. These nanoparticles act as carriers that can stably load tumor antigens and release them into the tumor microenvironment[190]. Antigen-presenting cells (such as dendritic cells) take up and process these tumor antigens before presenting them to T cells and inducing an immune response to the tumor antigen. Mannose-modified nanoparticles modulate immunosuppressive factors in the tumor microenvironment, thereby reducing T cell suppression[191,192,193,194,195]. In the tumor microenvironment, the presence of immunosuppressive factors (such as PD-L1, TGF-β, etc.) can inhibit the activation and function of T cells[196]. Nanoparticles modified with mannose can control the production and release of these immune-suppressing substances by interacting with specific receptors on the surface of tumor cells. This makes T cells less inhibited and more active, leading to more cell growth and activation[197]. Mannose-modified nanoparticles were also able to activate T-cell co-stimulatory signaling pathways. Co-stimulatory signaling is a key factor in T cell activation and proliferation, among which the CD28/B7 and CD40/CD40L signaling pathways play an important role in T cell activation and function[198,199,200]. Nanoparticles modified with mannose can turn on these co-stimulatory signaling pathways by attaching to the right receptors on the surface of T cells. This makes T cells' immune response stronger.
Mannose-modified lipid calcium phosphate nanoparticle vaccine, as an innovative immunotherapy method, has received extensive attention and research in recent years[201]. By modulating the tumor microenvironment, this vaccine can significantly enhance the anti-tumor immune response, providing new possibilities for tumor treatment. Several studies[202,203,204,205] have explored the treatment of this nanoparticle nucleic acid vaccine through clinical trials. These clinical trials typically involve the treatment of tumor patients in groups, with one group receiving the mannose-modified lipid calcium phosphate nanoparticle vaccine and the other group acting as a control group receiving either standard treatment or a placebo. The main purpose of the trial was to assess the effect of the vaccine on tumor growth in patients and the extent to which it activated the immune system[206]. By comparing the effects of treatment on different groups of patients, researchers can assess the effectiveness and safety of the vaccine. In clinical trials[207,208,209,210,211,212], researchers typically look at data on several aspects, including changes in tumor size, longer patient survival, and increased immune cell activity. These data can not only help judge the therapeutic effect of the vaccine but also provide an important basis for further optimization of the vaccine design and treatment plan(Figure 8).

4.2. Enhancement of Tumor Immune Response and Establishment of Immune Memory

Mannose-modified lipid calcium phosphate nanoparticle vaccine is a novel tumor immunotherapy method that can enhance the immune response to tumors by regulating the tumor microenvironment[213]. Studies[214,215,216,217,218,219,220] have shown that the vaccine can activate the body's immune system, promote the expression and recognition of tumor-associated antigens, and trigger a specific immune response against tumor cells. Through mannose modification, the vaccine can be more effectively taken up by antigen-presenting cells and improve its efficiency of antigen delivery in the lymph nodes, further activating immune cells such as dendritic cells and T cells and enhancing the potential of the immune response[221].
In the establishment of immune memory, the application of the vaccine also showed remarkable results[222,223,224,225]. It was found that after inoculation with mannose-modified lipid calcium phosphate nanoparticles, the body can form a long-term memory of tumor antigens[226]. This immune memory allows the body to recognize and clear tumor cells more quickly and efficiently during subsequent tumor invasion, thereby reducing the risk of tumor recurrence and metastasis. In addition, the establishment of immune memory also provides a solid foundation for subsequent immunotherapy, enabling the body to produce a more durable and powerful response to further treatment with tumor vaccines or other immunomodulators[227,228,229,230].
As a new way to treat tumors with immunotherapy, mannose-modified lipid calcium phosphate nanoparticle vaccine has shown great promise in improving the immune response to tumors and building immune memory[231,232,233,234,235]. This provides new ideas and strategies for the future treatment of cancer and is expected to play an important role in clinical practice, bringing more effective treatment effects and a better quality of life for patients[236,237,238,239,240]. The main determinants of drug resistance include heterogeneity of the tumor microenvironment, immunosuppressive mechanisms, and inefficiency of drug delivery[241]. A mannose-modified lipid calcium phosphate nanoparticle vaccine can improve the immunogenicity of tumor cells, regulate the tumor microenvironment, and promote an anti-tumor immune response by simulating natural antigen presentation(Figure 9).

4.3. Analysis of Immune Cell Infiltration in Tumor Tissue

Tumor tissue immune cell infiltration analysis is one of the important indicators to evaluate the effect of the mannose-modified lipid calcium phosphate nanoparticle vaccine on enhancing the anti-tumor immune response in the regulation of the tumor microenvironment[242]. Through immunohistochemical staining, flow cytometry, and other techniques, different types of immune cell infiltration in tumor tissues can be quantitatively analyzed, such as CD8+ T cells, CD4+ T cells, natural killer cells, and so on. It was found that the mannose-modified lipid calcium phosphate nanoparticle vaccine can significantly increase the amount of CD8+ T cell infiltration in tumor tissues, improve the ratio of CD8+/CD4+ T cells, and promote the transformation of the tumor immune microenvironment[243,244,245]. In addition, the vaccine can also effectively increase the degree of invasion of natural killer cells, thereby enhancing the clearance of tumor cells[246]. The analysis of tumor immune cell infiltration showed that a mannose-modified lipid calcium phosphate nanoparticle vaccine could regulate the tumor microenvironment and enhance the anti-tumor immune response significantly.

5. Enlightenment and Research Prospect of Preclinical Research

As a novel tumor immunotherapy strategy, mannose modified lipid calcium phosphate nanoparticle vaccine has shown great potential in preclinical studies[247,248,249,250]. Through in-depth investigation of its mechanism of action, we found that the vaccine can effectively regulate the tumor microenvironment and enhance the anti-tumor immune response of the body. Studies[251,252,253] have shown that mannose-modified nanoparticles can promote uptake and endocytosis of tumor cells through specific targeting, thereby improving the efficiency of antigen delivery and activating the activity of tumor-associated antigen-specific T cells. In addition, the vaccine can also induce immune cells in the tumor microenvironment, such as plasma cells and dendritic cells, to release pro-inflammatory factors, and inhibit the function of immunosuppressive cells, thereby promoting the activation and expansion of T cells, enhancing the killing ability of cytotoxic T lymphocytes, and finally realizing the effective elimination of tumors.

6. Research Future Prospects

In future studies, we can further optimize the formulation and preparation process of mannose-modified lipid calcium phosphate nanoparticle vaccine to improve its stability and bioavailability in vivo, thereby enhancing its anti-tumor immunotherapy effect[254]. In addition, the vaccine could be explored in combination with other tumor therapies, such as chemotherapy, radiotherapy and immune checkpoint inhibitors, to achieve better therapeutic outcomes. In addition, it is possible to design personalized treatment regiments for different types and stages of tumors and verify their safety and efficacy through preclinical and clinical studies. In general, mannose modified lipid calcium phosphate nanoparticles vaccine has broad application prospects in the field of tumor immunotherapy, and is expected to become one of the important strategies for tumor therapy in the future.

7. Conclusions

Mannose-modified nanoparticles can effectively regulate the tumor microenvironment, inhibit tumor growth, and enhance the infiltration of immune cells. This vaccine not only induces a strong and long-lasting antigen-specific T cell response but also activates anti-tumor effector cells such as natural killer cells and macrophages. In addition, after reviewing the literature, we found that the vaccine could induce antibody production and thus enhance humoral immune response; namely, the mannose-modified lipid calcium phosphate nanoparticle vaccine showed good potential in regulating tumor microenvironment, promoting immune cell infiltration, and inducing antibody and T cell responses, providing a new idea and strategy for tumor immunotherapy.

Author Contributions

L.W. analyzed the data and wrote the paper; J.Y. designed and guided the research; X.Q., W.H. and S.W. collected and downloaded the data in our research. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Research and Development of Intelligent Surgical Navigation and Operating System for Precise Liver Resection (2022ZLA006), the Start-up Fund for Talent Researchers of Tsinghua University (10001020507).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Bio-3D printing technology and nanocarriers combined application platform.
Figure 1. Bio-3D printing technology and nanocarriers combined application platform.
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Figure 2. Nanoparticle carrier penetrates meninges to target and kill tumors in mouse brain metastatic tumor model.
Figure 2. Nanoparticle carrier penetrates meninges to target and kill tumors in mouse brain metastatic tumor model.
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Figure 3. Photoacoustic imaging (PAI) process of mannose modified lipid calcium phosphate nanoparticle vaccine in mouse model.
Figure 3. Photoacoustic imaging (PAI) process of mannose modified lipid calcium phosphate nanoparticle vaccine in mouse model.
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Figure 4. Schematic illustration of lipid calcium phosphate nanoparticles measuring oxidative stress using photoacoustic imaging (PA).
Figure 4. Schematic illustration of lipid calcium phosphate nanoparticles measuring oxidative stress using photoacoustic imaging (PA).
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Figure 5. Schematic diagram of interaction mechanism between Tumor mRNA-LNPs Vaccine and immune system.
Figure 5. Schematic diagram of interaction mechanism between Tumor mRNA-LNPs Vaccine and immune system.
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Figure 6. Schematic diagram of mannose purification, biotransformation and covalent modification techniques.
Figure 6. Schematic diagram of mannose purification, biotransformation and covalent modification techniques.
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Figure 7. Mannose-LNP-CaP nanoparticles target carcinogenic long non-coding RNA for cancer therapy.
Figure 7. Mannose-LNP-CaP nanoparticles target carcinogenic long non-coding RNA for cancer therapy.
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Figure 8. Summary diagram of clinical trial phase related to nanoparticle vaccine.
Figure 8. Summary diagram of clinical trial phase related to nanoparticle vaccine.
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Figure 9. Schematic diagram of determinants of Cancer Drug Resistance and Mannose-LNP-CaP Therapy.
Figure 9. Schematic diagram of determinants of Cancer Drug Resistance and Mannose-LNP-CaP Therapy.
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