The Role of Nanotechnology in Improving the Parasite’s Antitumor Effects

1.Context
Cancer treatment is one of the significant medical challenges of today [1]. Despite significant advances in the diagnosis and treatment of cancer, many patients still suffer from insufficient treatment response and severe side effects [2, 3]. Immunotherapy has been proposed as an innovative cancer treatment method that fights cancer cells by stimulating the body’s immune system. Cancer immunotherapy, which has been widely used in the last few years, has the primary goal of stimulating the body’s immune system in such a way that it can identify and destroy cancer cells. However, limited efficacy and variable responses in different patients have revealed the need to improve and strengthen these methods [4, 5].
For all its advantages, immunotherapy still faces several challenges [6]. Many patients do not respond well to this procedure; in some cases, overly immune responses can lead to serious side effects [7]. Therefore, it is necessary to find ways to increase the efficiency and reduce the side effects of this method. In this regard, using parasites as immune system stimulants is one of the new and promising approaches. Due to their complex and long-term interactions with the host’s immune system, parasites can modulate and enhance immune responses.
In recent years, there has been some shreds of evidence that parasites can effectively enhance the body’s immune responses. Parasites such as Echinococcus granulosus, Trichinella spiralis, Trypanosoma cruzi, and Toxoplasma gondii have attracted the attention of researchers due to their unique abilities to interact with the immune system [8]. These parasites can help increase the efficiency of immunotherapy in cancer treatment by stimulating and modulating immune responses. These parasites’ biological characteristics and specific mechanisms have made them potential tools to enhance immunotherapy (Table 1).

2. Data Acquisition
E. granulosus, the causative agent of hydatidosis, has molecules and proteins that stimulate the body’s immune responses. These features have caused CE to be proposed as a potential adjuvant in cancer immunotherapy. Research has shown that different components of E. granulosus can help strengthen therapeutic effects and reduce side effects [9, 10]. The surface proteins and components of E. granulosus can stimulate immune responses, which can be used as a booster in immunotherapy methods [11].
T. spiralis, another parasite known for enormously stimulating the host’s immune system, also has excellent potential for use in immunotherapy treatments. T. spiralis can modulate and strengthen the body’s immune responses by producing specific molecules, improving treatment results. T. spiralis’s ability to generate a strong and sustained immune response has made it an attractive option for researchers in the field of cancer immunotherapy [12, 13]. Studies have shown that T. spiralis-derived molecules can effectively help stimulate the immune system [14, 15].
T. cruzi, the causative agent of African sleeping sickness, and T. gondii, the causative agent of toxoplasmosis, have also received attention for their unique abilities to stimulate the immune system [16]. Using different molecular and cellular mechanisms, these parasites can strengthen the body’s immune responses and help increase the efficiency of immunotherapy. The surface proteins and antigens of these parasites are designed in such a way that they can improve the body’s immune responses. These parasites and their derived molecules can be studied and used as a complementary method in cancer immunotherapy [17].
In addition, nanocoatings, one of the new developments in medicine, can play an essential role in improving the efficiency and safety of these methods [18]. Nanocoatings can minimize side effects and improve therapeutic outcomes by providing precise and effective delivery of immunostimulating molecules [19, 20]. This new technology can act as an intelligent carrier to deliver effective molecules to desired locations in the body. Combining parasites and nanocoatings can be a multidimensional and practical approach to cancer treatment and significantly improve treatment results. Hence, the current study aims to review this field’s advances, challenges, and future perspectives. Using parasites and nanocoatings as a new and multidimensional strategy can open new horizons in cancer treatment and lead to more advanced treatment methods.

3. Results
3.1. E. granulosus
E. granulosus is a worm parasite that causes hydatidosis in humans and animals. E. granulosus is usually transmitted to humans through the eggs in the feces of dogs and creates hydatid cysts in various body organs, including the liver and lungs. Recent studies have shown that E. granulosus can be influential in modulating and strengthening the body’s immune system and can be proposed as a new tool in cancer treatment [21]. One of the main mechanisms of the anticancer effects of E. granulosus is the production of immunomodulatory molecules that can regulate the body’s immune responses [10]. These molecules include proteins and peptides produced by the parasite and can alter the activity of immune cells such as macrophages, dendritic cells, and lymphocytes. For example, one of these molecules, E. granulosus antigen B protein (EgAgB), can stimulate the production of inflammatory cytokines such as interleukin-12 (IL-12) and interferon-gamma (IFN-γ), which can enhance anti-cancer immune responses [9, 22]. E. granulosus can help destroy cancer cells by stimulating cellular immune responses, especially killer T cells (CTLs). Studies have shown that the parasite’s antigens can increase the proliferation and activity of T cells. For example, in one study, the injection of E. granulosus antigens into mice with melanoma caused a significant increase in the number and activity of killer T cells, which led to a decrease in the size of the tumors [23].
Another mechanism of the anticancer effects of E. granulosus is the inhibition of signaling pathways related to the growth and survival of cancer cells [24]. For example, proteins extracted from hydatid cysts can inhibit PI3K/Akt and MAPK signaling pathways, which are active in many types of cancer and play an essential role in cancer cell survival. Inhibition of these pathways can reduce the proliferation of cancer cells and increase their sensitivity to apoptosis. In addition to enhancing adaptive immune responses, E. granulosus can also enhance innate immune responses [25]. For example, E. granulosus can increase the production of neutrophils and macrophages and strengthen their activity. Neutrophils and macrophages play an essential role in identifying and destroying cancer cells, and enhancing their activity can help reduce the growth and spread of tumors [26]. For example, in one study, injecting E. granulosus antigens into mice with colorectal cancer led to increased macrophage activity and a significant reduction in tumor size.

3.2. T. spiralis
T. spiralis is a nematode parasite that causes trichinosis in humans and animals. T. spiralis enters the body by consuming contaminated raw or undercooked meat, multiplies in the small intestine, and its larvae migrate to the skeletal muscles through the bloodstream. In recent years, several studies have investigated the role of T. spiralis in stimulating and modulating the immune system, which can be used as a new approach to cancer treatment [12, 27]. T. spiralis can stimulate anti-tumor immune responses. One of the key molecules of T. spiralis is excretory-secretory (ES) products, which are secreted by T. spiralis larvae. These molecules can increase dendritic cells’ activity and improve the antigen presentation to T cells. The activated T cells can then directly target and destroy cancer cells [28]. For example, in one study, injecting ES products into mice with lung cancer led to reduced tumor growth and increased survival. T. spiralis can balance inflammatory and anti-inflammatory immune responses by modulating immune pathways [29]. T. spiralis can increase the production of inflammatory cytokines such as IL-12 and IFN-γ and simultaneously decrease the production of anti-inflammatory cytokines such as interleukin-10 (IL-10) [30]. This fine-tuning of immune pathways can help reduce tumor growth and inhibit metastasis. For example, a study showed that T. spiralis can inhibit NF-κB signaling pathways and thereby reduce the proliferation of cancer cells.
T. spiralis can also enhance innate immune responses. Macrophages, neutrophils, and NK cells are innate immune cells that identify and destroy cancer cells. T. spiralis can increase the production and activity of these cells [31]. For example, in one study, injecting T. spiralis larvae into mice with colorectal cancer led to increased macrophage activity and a significant reduction in tumor size. T. spiralis can change the tumor microenvironment into an immunogenic environment [15]. By stimulating the production of different cytokines and chemokines, T. spiralis can increase the penetration of immune cells into the tumor. This process can lead to improved anti-tumor immune responses and reduced tumor growth. For example, a study showed that T. spiralis can inhibit the growth of melanoma by increasing the penetration of T cells and macrophages into the tumor.

3.3. T. cruzi
T. cruzi is a protozoan parasite that causes Chagas disease in humans. T. cruzi has significant potential to stimulate and modulate the body’s immune system, which could be helpful in cancer treatment [32]. One of the main mechanisms of the anti-cancer effects of T. cruzi is the stimulation of anti-tumor immune responses. T. cruzi can increase the activity of immune cells, such as dendritic and T cells, by producing and secreting immunomodulatory molecules [33]. For example, T. cruzi surface proteins, such as surface glycoproteins (TSGP), can enhance the activity of dendritic cells and improve the presentation of antigens to T cells. This process can increase the proliferation and activity of killer T cells that directly target and destroy cancer cells [34].
T. cruzi can apply its anticancer effects by inhibiting the signaling pathways related to the growth and survival of cancer cells [34]. For example, some proteins extracted from T. cruzi can inhibit PI3K/Akt and MAPK signaling pathways, which are active in many types of cancer and play an essential role in the survival of cancer cells. Inhibition of these pathways can reduce the proliferation of cancer cells and increase their sensitivity to apoptosis [35]. T. cruzi can balance inflammatory and anti-inflammatory immune responses by modulating the body’s immune system. T. cruzi can increase the production of inflammatory cytokines such as IL-12 and IFN-γ and simultaneously decrease the production of anti-inflammatory cytokines such as IL-10 [36]. This fine-tuning of immune pathways can help reduce tumor growth and inhibit metastasis. For example, a study showed that T. cruzi can inhibit NF-κB signaling pathways and thereby reduce the proliferation of cancer cells.
In addition to enhancing adaptive immune responses, T. cruzi can also enhance innate immune responses. Macrophages, neutrophils, and NK cells are innate immune cells that identify and destroy cancer cells [37]. T. cruzi can increase the production and activity of these cells. For example, in one study, injection of T. cruzi into mice with lung cancer led to increased activity of macrophages and neutrophils and a significant reduction in tumor size. T. cruzi can provide conditions for more effective immune responses by altering the tumor microenvironment. By stimulating the production of chemokines and adhesion molecules, T. cruzi can increase the penetration of immune cells into the tumor [38]. 

3.4. T. gondii
T. gondii is a protozoan parasite that causes toxoplasmosis in humans and animals. It enters the body through food or water contaminated with oocysts or mother-to-fetus transmission. T. gondii can cause cysts in different body tissues, such as the brain, eyes, and skeletal muscles. In recent years, several studies have investigated the modulating effects of T. gondii on the body’s immune system and its possible applications in cancer treatment [39]. T. gondii can exert its anticancer effects by stimulating antitumor immune responses. T. gondii can increase dendritic and T cells’ activity by producing and secreting immunomodulatory molecules such as secretory proteins (SAGs and GRAs). For example, T. gondii surface antigens (SAG1 and SAG3) can activate dendritic cells and present antigens to T cells, leading to increased IFN-γ production and stimulation of antitumor immune responses. In one study, injection of T. gondii antigens into mice with ovarian cancer resulted in a significant reduction in tumor size and increased survival of the mice.
T. gondii can exert its anticancer effects by inhibiting signaling pathways related to the growth and survival of cancer cells. Some proteins of T. gondii can inhibit PI3K/Akt and MAPK signaling pathways, which are active in many types of cancer and play an essential role in the survival of cancer cells [40]. Inhibition of these pathways can reduce the proliferation of cancer cells and increase their sensitivity to apoptosis. For example, in one study, injecting proteins extracted from T. gondii into mice with liver cancer inhibited the PI3K/Akt pathway and reduced tumor growth.
T. gondii can balance inflammatory and anti-inflammatory immune responses by modulating the body’s immune system [41]. A study showed that T. gondii can inhibit NF-κB signaling pathways and thereby reduce the proliferation of cancer cells. In addition to enhancing adaptive immune responses, T. gondii can also enhance innate immune responses [42]. T. gondii can increase the production and activity of these cells. For example, in one study, injection of T. gondii into mice with lung cancer led to increased activity of macrophages and neutrophils and a significant reduction in tumor size.
T. gondii can alter the tumor microenvironment to provide conditions for more effective immune responses [43]. By stimulating the production of chemokines and adhesion molecules, T. gondii can increase the penetration of immune cells into the tumor. This process can lead to improved anti-tumor immune responses and reduced tumor growth. For example, in one study, injection of T. gondii into mice with melanoma led to increased T cells and macrophage infiltration into the tumor and inhibition of tumor growth [44].

3.5. Nanotechnology and nanocoating
As a new field in science, Nanotechnology has brought about huge changes in medicine and has vulnerable applications in diagnosis, crises, and diseases. This technology, using nanoparticles and materials in nanometers, allows the design of targeted systems for drug delivery, gene therapy, and tissue repair. For example, lipid and polymer nanoparticles as drug carriers help increase the bioavailability of drugs, reduce side effects, and increase their effectiveness. In disease diagnosis, nanobiosensors and gold and silver nanoparticles are naturally used for rapid and sensitive diagnosis of diseases such as cancer, infectious diseases, and metabolic disorders. Additionally, nanoparticle systems such as magnetic nanoparticles are used in the therapy field to guide drugs to the precise location of tumors and treat cancer. In addition, nanotechnology has played a key role in developing new vaccines, including RNA vaccines with lipid nanocarriers, a prime example of which is the production of COVID-19 vaccines. These advances demonstrate the enormous potential of nanotechnology in improving the quality of life and developing personalized therapies that are shaping the horizons of modern medicine.
Nanocoatings, especially lipid nanocoatings, play a vital role in the modern world of medicine and pharmaceuticals. Due to their unique properties, these coatings with nano dimensions (usually less than 100 nm) and their particular structure have become powerful tools for drug delivery and enhancing biological functions [45, 46]. Lipid nanocoatings, in particular, comprise lipid layers similar to cell membranes’ structure. For this reason, they can penetrate and interact with body cells and tissues. These properties allow them to effectively deliver drugs to the precise points of interest and enhance their therapeutic and preventive effects. In drug delivery, lipid nanocoatings can quickly enter cells and target the target tissues due to their structural similarity with cell membranes [47]. This capability is critical in targeted drug delivery, where there is a need for high precision in delivering the drug to specific parts of the body. Using lipid nanocoatings, drugs can be directly and accurately delivered to specific tissues such as cancer tumors. This reduces the amount of drugs needed and adverse side effects in other parts of the body, which helps improve the patient’s quality of life and increases the treatment’s effectiveness.
In addition to targeted drug delivery, lipid nanocoatings are particularly effective in enhancing anti-parasitic antigens [48]. These nanocoatings can effectively transfer specific antigens to the target tissues to stimulate the body’s immune system and fight against parasites. This technology can be particularly effective in diseases caused by parasites that require strong immune system stimulation. By covering antigens and presenting them to specific body areas, lipid nanocoatings help strengthen the immune response and increase the body’s ability to fight against parasites. In cancer treatments, lipid nanocoatings play a crucial role [49]. These nanocoatings can deliver anti-cancer drugs to cancer cells in a targeted manner and thus reduce the dose of drugs used. With this technology, drugs are precisely transferred to the desired sites, reducing side effects in healthy tissues and increasing the treatment’s effect on cancerous tumors. In addition, lipid nanocoatings can help deliver drugs to complex and inaccessible environments such as high-grade tumors and improve cancer treatments.
Lipid nanocoatings also have a high potential for improving therapeutic capabilities and disease prevention. By providing drugs in a controlled and targeted manner, these coatings can be used as practical tools to reduce drug side effects and increase the impact of various treatments. This technology is constantly evolving, and it is expected that shortly, with further developments, it will offer more capabilities in treating diseases and improving people’s health. In general, lipid nanocoatings, with their unique properties, are considered an advanced technology in pharmaceuticals and medicine. Due to their high capabilities in improving drug delivery and strengthening biological functions, these coatings can help transform treatment methods and improve patients’ quality of life. Due to the continuous progress in this field, it is hoped that lipid nanocoatings will play broader roles in improving treatments and combating diseases shortly and will be recognized as crucial tools in various fields of medicine and pharmaceuticals (Figure 1, Table 2).

3.6. Future challenges
Parasite antigens with anticancer properties have attracted much attention as a new and promising field in anticancer treatments. These antigens, usually derived from specific proteins or molecules in parasites, have been explored in recent research as a new strategy in cancer treatment due to their ability to stimulate a robust immune response and direct immune cells to cancer tumors. These antigens can help activate the immune system and increase the body’s sensitivity to cancer tumors. Still, this process requires a suitable substrate for effectively transferring these antigens to the target sites. One of the main challenges in using parasite antigens as anti-cancer treatments is the practical and targeted delivery to specific body areas. Nanocoatings can provide an effective solution to this problem. By using lipid nanocoatings, these antigens can be precisely targeted to tumoral cells, which helps to increase the therapeutic effect and reduce side effects. Nanocoatings, with their properties such as tissue penetration and controlled release of active substances, can help improve the delivery of parasite antigens and enhance their anticancer properties.
However, using nanocoatings to enhance the effects of parasite antigens is associated with several challenges. One of these challenges is to ensure the nanocoatings’ stability during the transfer to the target site. Nanocoatings should be designed to resist physiological conditions such as pH and enzymes to effectively deliver antigens to their destination [50]. Furthermore, optimizing the size and surface of nanocoatings to increase their absorption and reduce their excretion from the body is another critical issue that should be considered. Another challenge is managing possible immune reactions to nanocoatings and transferred antigens. Nanocoatings or antigens may induce unwanted immune responses that can negatively affect the therapeutic effect. It is of great importance to design nanocoatings in a way that minimizes side effects and directs immune responses to impact treatment positively. In addition, the cost of production and scalability of nanocoatings can also be a severe obstacle to their widespread use. Finally, more research is needed to understand the mechanisms of action of parasite antigens and optimize nanocoating technologies. This research can lead to the design of new methods for more effective and safer transfer of antigens and improve the effectiveness of anti-cancer treatments. With more scientific and technological advances, it is hoped that nanocoatings and parasite antigens can lead to more successful treatments based on new technologies in dealing with cancer (Table 3).

4. Conclusion
Parasite antigens with anticancer properties have attracted much attention as a new approach to cancer treatment. These antigens can help activate a robust immune response against cancer tumors, but the main challenge in their practical use is precise and targeted delivery to the desired areas. Lipid nanocoatings can play a vital role in this field due to their unique properties, such as tissue penetration and controlled drug release. Using nanocoatings, it is possible to deliver targeted parasite antigens to tumoral cells, improving the effectiveness of anticancer treatments and reducing side effects. However, there are still challenges, including the stability of nanocoatings during the transduction pathway, management of immune reactions, and production costs. Research and scientific advances in this field can improve the design of nanocoatings and increase the efficiency of treatments based on parasite antigens.

Acknowledgements
We would like to thank the Ferdowsi University of Mashhad for supporting us.

Compliance with ethical guidelines
There were no ethical considerations to be considered in this research.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Authors' contributions
Conceptualization, and supervision: Alireza Omranzadeh; Methodology: Samira Amini Ahour, Sara Eghbalkharazi, and Neda Mohammadi; Formal analysis and investigation: Mahsa Fakhraee, Nilufar Hajizadeh Shahrak, and Alireza Omranzadeh; Writing the original draft: Amirhossein Davoudnezhad Dehsorkhi and Shimen Gevargiz Sangar; Review, editing, and final approval: All authors.

Conflict of interest
The authors declared no conflict of interest.

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