A Comprehensive Review of Nanoadjuvants in Cancer Vaccines and Their Immunomodulatory Role and Clinical Applications

1. Context
Avaccine is widely recognized as one of the most effective ways to prevent and treat disease, and it has been used for a very long time to combat infectious diseases worldwide. Recently, this approach has been applied to a broad range of new applications, including cancer treatment [1]. Cancer is one of the most critical diseases worldwide, and several strategies have been used to fight it, with immunotherapy employed as one of the most effective techniques [2, 3]. Vaccines against cancer serve to stimulate the body’s immune system to recognize and destroy cancer cells when they are injected [4]. While infectious disease vaccines, which have achieved wide dissemination over the past few decades, often face obstacles such as the lack of a robust and sustained immune response, cancer vaccines have not been as successful [5]. In most cases, these problems are caused by cancer antigens, which cannot generate strong immune responses and therefore fail to stimulate the immune system effectively [6]. Cancer cells are naturally recognized and destroyed by the body’s immune system as soon as they become abnormal. Despite this, cancer cells may escape immune detection because they closely resemble normal, non–cancerous cells [7]. There is also a tendency for tumor microcellular environments to be regulated in such a way as to suppress immune reactions. The lack of these characteristics makes cancer vaccines alone incapable of eliciting an immune response that is effective against cancer. Hence, it is a matter of great concern that more and more research is being conducted to make cancer vaccines more effective.
Adjuvants are one of the most important strategies that can be used to enhance immune responses against cancer antigens. An adjuvant is a substance added to antigens in vaccine formulations to enhance the immune response to these antigens. As a conventional vaccine, aluminum and oil emulsions are widely used as adjuvants to enhance the immune response. Despite this, these compounds tend to be ineffective in fighting cancer antigens and cause weak immune responses in the body. This has created a need for new and more effective adjuvants in cancer vaccines. Meanwhile, nanotechnology has been proposed as an innovative and powerful tool to improve cancer treatment and diagnosis [8, 9]. Nanoadjuvants are nanoscale materials that carry cancer antigens and deliver them to specific areas of the body. These nanoparticles’ small size and large surface area allow them to interact directly with the immune system. This creates a stronger immune response. In addition, nanoadjuvants optimize their structure and function to interact with cancer antigens and enhance immune responses precisely [10].

2. Data Acquisition
Nanoadjuvants can improve immune responses through various mechanisms. One of these mechanisms is the controlled delivery of antigens to dendritic cells (DCs) [11]. DCs serve as the main presenters of antigens to T cells and play a central role in the stimulation of immune responses. Nanoadjuvants are able to deliver cancer antigens to these cells in a targeted manner and increase the efficiency of immune responses. In addition, nanoadjuvants can enhance innate and adaptive immune responses by activating inflammatory pathways and producing cytokines [12, 13].
Another advantage of using nanoadjuvants is reducing the required vaccine dose and side effects [14]. By using nanoparticles, antigens can be delivered in a concentrated form and at a lower dose, thus reducing unwanted side effects. Also, nanoadjuvants can protect vaccines against premature degradation in the body and increase their stability and efficiency [15].
Although nanoadjuvants have shown promising results in preclinical stages and early studies, there are still many challenges for this technology to enter the clinical arena. One of these challenges is nanoparticle safety and toxicity issues [16]. More research must ensure that these nanoscale materials do not accumulate in the body in the long term and cause serious side effects. In addition, developing efficient methods for producing and scaling up these nanoadjuvants is another existing challenge. Despite these challenges, nanoadjuvants are recognized as one of the most important new tools in developing cancer vaccines, and more research is being conducted in this field [17]. Advances in this field can lead to significant improvements in the effectiveness of cancer vaccines and increased survival rates in cancer patients. Combining the knowledge of nanotechnology and immunology can open new horizons in cancer treatment, and nanoadjuvants will play a key role in realizing this goal [18]. This review aims to explore the role of nanoadjuvants in cancer vaccines, highlighting their potential to enhance immune responses and improve vaccine efficacy. It seeks to examine the immunomodulatory mechanisms of various nanoadjuvants and their impact on antigen presentation, T-cell activation, and immune memory. Additionally, this review aims to discuss the clinical applications of nanoadjuvant-based cancer vaccines, analyzing current advancements, challenges, and future prospects in cancer immunotherapy.

3. Mechanisms of Action of Nanoadjuvants in Modulating Immune Responses
Using the unique properties of nanoparticles as adjuvants, nanoadjuvants create an immunostimulatory effect by regulating and enhancing the immune response. It is important to appreciate that targeting antigen delivery to the immune system is one of these nanoparticles’ most important mechanisms of action [19]. Nanoadjuvants are easily absorbed by immune cells because of their small size and large surface area, making them highly effective in interacting with these cells [20]. In addition, DCs play an important role in capturing antigens, processing them, and presenting them to T cells [21]. As a result of nanoadjuvants, antigens are directly transferred to these cells, which increases antigen presentation. Nanoadjuvants activate DCs by presenting antigens to them so that they can recognize the antigen. DCs mature after absorbing nanoparticles and antigens and produce cytokines and stimulatory molecules, which stimulates T cells [22]. Activating T cells is one of the main goals of cancer vaccines because these cells recognize and destroy cancer cells. Nanoadjuvants create a more effective immune response by creating a favorable environment for activating DCs and thus promoting T cell activation [23].
In addition to directly stimulating DCs and T cells, nanoadjuvants also induce innate immune responses. Nanoparticles activate innate immune system signaling pathways, leading to the production of interferons and inflammatory cytokines [24]. These cytokines are essential for strengthening adaptive immune responses and provide a suitable environment for stimulating and increasing immune cells [25]. In particular, nanoadjuvants can activate pathways such as Toll-like receptors (TLRs), which stimulate innate and adaptive immune responses. Nanoadjuvants enhance B-cell responses and antibody production. Humoral immune responses, including B-cell antibody production, are critical to long-term immunity and fighting cancer cells [26]. By presenting antigens to B cells and improving their interaction with T helper cells, nanoadjuvants increase antigen-specific antibody production. These antibodies bind to cancer cells and mark them for destruction by other immune cells [27].
Developing immune memory is one of the basic goals of any vaccine, and nanoadjuvants play a significant role in creating this immune memory. By enhancing primary immune responses, nanoparticles activate memory T and B cells [28]. These memory cells remain in the body after initial exposure to the antigen. In the case of re-exposure to cancer antigens, they generate a faster and stronger immune response [29]. Creating this immune memory can lead to lasting effects of cancer vaccines and reduce the possibility of disease recurrence. Nanoadjuvants can also alter the microcellular environment of tumors, making it more suitable for immune system activity [30]. In many tumors, the microcellular environment is immunosuppressive, preventing immune cells from penetrating and destroying cancer cells. Nanoadjuvants can improve immune cell penetration and activity conditions by stimulating cytokine production and altering the cellular composition of the tumor environment [31]. This increases the penetration of killer T cells into the tumor and increases the rate of cancer cell destruction.
It must also be considered that nanoadjuvants possess unique physical, chemical, and biological properties. This makes them effective carriers for transporting pharmaceutical compounds or immunomodulatory molecules [32]. In addition to delivering antigens to the patient, nanoadjuvants can simultaneously deliver small molecules that inhibit or stimulate the immune system. This affects multiple immune pathways simultaneously [33]. This is one of the biggest advantages of nanoadjuvants, which improve the efficacy of cancer vaccines, regulate immune responses, and target immune responses precisely [34]. Nanotechnology techniques allow nanoparticles with specific physical and chemical properties to target specific cells and tissues in the body. This allows researchers to deliver nanoadjuvants precisely to tumor or lymph node sites, maximizing cancer vaccine efficacy [35]. This fine-tuning results in fewer side effects and a stronger, more stable immune response (Figure 1).

4. Preclinical Studies and Experimental Models
The results of preclinical studies play a crucial role in determining the efficacy and safety of nanoadjuvant therapy in cancer vaccines. Animal models are mainly used to conduct these studies, allowing researchers to test the immunogenic effects of nanoadjuvant on living organisms during complex research. Several animal models have been developed, such as lab mice, which can be used to study cellular and humoral immune responses to cancer vaccines [37]. This is because their immune structures are similar to the human immune system. It is possible to determine how nanoparticles are transported, how DCs absorb them, and whether it is possible to enhance immune responses against tumors through preclinical studies [38]. In terms of preclinical studies, one of the most important benefits of using animal models is that researchers can determine whether nanoadjuvants can simultaneously affect both adaptive and innate immune responses, which are among the most critical components of preclinical research [27]. It has been demonstrated in long-term studies that certain nanoadjuvants, in addition to enhancing killer T cells, may also reduce the number of regulatory T cells, which generally cause immunosuppression in animal tumor models [39]. These changes can alter the microcellular environment of the tumor in favor of the immune response and ultimately increase the probability of tumor regression. Such results in animal models indicate the high potential of these nanoadjuvants to enhance cancer vaccine effectiveness in humans.
Various animal models evaluate nanoadjuvant performance in cancer vaccines, including mouse models, dog models, and even non-human primate models such as monkeys. The advantages and disadvantages of each of these models can be found in their descriptions [40]. Regarding preclinical models, mice are among the most popular because of their easy accessibility and low cost. However, it is important to remember that some of the observed responses may not be fully reproducible in humans due to significant differences in the immune system between mice and humans [41]. A large animal model, such as dogs or monkeys, can provide more accurate results because their immune systems are more similar to humans than those of smaller animals. Even though they are more complex and expensive, they are also more suitable. Several recent preclinical studies on mouse models have shown that nanoadjuvants can significantly increase the survival rates of mice carrying tumors [42, 43]. Among the studies, one of the most successful and exciting was a study using a nanoadjuvant based on lipid nanoparticles in combination with tumor antigens to treat mice with melanoma. This nanoadjuvant induced an increase in the proliferation of killer T cells at the site of the tumor, according to the results of this study. The process also resulted in stable immune memory, which prevented the tumor from regrowing in the long run. Based on these results, nanoadjuvants can produce lasting immunity against tumors, even when administered as a single dose.
In addition to evaluating their effectiveness, preclinical studies also investigate the safety and toxicity of nanoadjuvants [44]. Although nanoparticles can quickly spread in the body due to their small size and unique properties, these properties can lead to their accumulation in sensitive organs such as the liver and kidneys. Animal studies have shown that nanoparticle accumulation in specific tissues can cause inflammation and cellular damage. Therefore, it is necessary to investigate the toxicity of nanoadjuvants in animal models to evaluate their safety and optimal dosage and avoid side effects in clinical studies [45]. Tumor models in preclinical studies can be used in two ways: Xenograft and induced tumor models. Cancer cells are transplanted directly into animal bodies in transplanted tumor models. In induced tumor models, chemical or genetic agents are applied to create the tumor. Each of these models responds differently to nanoadjuvants. Transplanted tumor models are more widely used due to their ease of establishment and faster reaction control. Still, induced tumor models can provide more realistic results due to their greater similarity to the body’s natural tumor formation process [46].
Preclinical studies on nanoadjuvants are often conducted in combination with other immunotherapies [47]. For example, some studies have shown that combining nanoadjuvants with immune inhibitors such as anti-PD-1 or anti-CTLA-4 can strongly enhance the immune response to tumors. These compounds effectively prevent immune suppression by tumors and increase killer T cell penetration into the tumor. These combined approaches can ultimately lead to more effective treatment strategies that are safer and more effective than traditional methods. Overall, preclinical studies on nanoadjuvants provide valuable information about their mechanisms of action, safety, and efficacy in animal models. These studies provide the necessary foundation to enter clinical phases [48]. They can help researchers design more efficient and safer nanoadjuvants for cancer vaccines. However, due to the differences between animal and human immune systems, preclinical results should be interpreted cautiously. Confirmation of these findings in human experimental studies is essential. Such an approach can ensure the successful transfer of nanoadjuvants to clinical applications (Table 1).

5. Future Challenges
In developing nanoadjuvants for cancer vaccines, one of the most critical challenges is the inherent complexity involved in the formulation of nanoparticles and the precise control of their size, shape, and surface area. As a result of these characteristics, nanoadjuvant efficacy and safety are directly influenced, and mass production of these products at a large scale poses a challenge. Furthermore, when it comes to the production process and the precise characterization of nanoadjuvants, they must be designed to meet stability and reproducibility specifications [49]. It is essential to recognize that this can be impacted by technological limitations in certain cases. Similarly, nanoparticles can have non-uniform sizes or surfaces, resulting in a drastic change in their performance and a possible escalation of side effects if these issues are not addressed. Developing nanoadjuvants is one of the most significant challenges scientists face due to safety concerns. Even though many preclinical studies have demonstrated that nanoparticles can benefit human health, concerns remain regarding their long-term toxicity to the human body after intake [50]. Depending on which nanoparticles are ingested, they may accumulate in the body and cause inflammation and damage to vital tissues such as the liver, kidneys, or lungs. Studies over a long period are required to accurately evaluate nanoadjuvant adverse effects. Furthermore, it is imperative to stress that the differences between the human immune system and those of animal models make it difficult to generalize preclinical results to humans. This highlights the need for extensive clinical trials.
It is also important to note that the high cost of production and the lack of commercialization of nanoadjuvant technology are among the challenges to developing nanoadjuvants. Nanoparticle production involves advanced technologies and expensive raw materials. This can impede the introduction of these products to a broad market because of technological barriers. Additionally, these difficulties are exacerbated by the costs associated with clinical research and regulatory agencies. If nanoadjuvants prove to be effective in clinical trials, their improved efficacy and reduced need for more expensive treatment methods could lead to a decrease in the cost of cancer vaccines, thereby reducing overall treatment costs. Furthermore, nanoadjuvant development has been hindered by several regulatory issues and challenges associated with approvals. Nanoadjuvants have yet to be approved by many regulatory bodies, including the United States Food and Drug Administration (FDA), which oversees the approval of drugs and pharmaceuticals. Considering the complexity associated with evaluating nanoparticle safety and effectiveness, adhering to current regulatory requirements may not be feasible based on existing criteria. To facilitate the approval and market entry of these technologies as quickly and efficiently as possible, it is essential to develop new and integrated guidelines for evaluating nanoadjuvants.
Moreover, future development of nanoadjuvants is expected to focus on improving nanoparticle design and manufacturing to enhance safety and effectiveness. This will be done using new combinations of nanomaterials and by combining nanoadjuvants with other immunotherapy approaches. This will further improve nanoadjuvant efficacy and safety. Currently, researchers are designing nanoparticles capable of enhancing the immune response, possessing minimal side effects, and targeting cancer cells specifically. In this regard, technologies like nanoparticles coated with targeted ligands or antibodies may penetrate tumors more effectively. The immune system may generate more precise responses. In addition to recent advances in bioinformatics and computer modeling, advances in nanotechnology have opened up new possibilities for designing and evaluating nanoadjuvants. Using these technologies, researchers can simulate nanoadjuvant performance and safety, and predict their behavior before conducting experiments. This helps determine whether they perform as expected. Significant reductions in nanoparticle development costs have been achieved through this method, and the design process can be accelerated. Furthermore, computational models can help assess possible risks and side effects of nanoadjuvants more quickly and accurately.
In the future, there is a possibility of integrating nanoadjuvants with other new technologies, such as gene editing and immunotherapy using chimeric antigen receptor (CAR) T cells, within a nanoadjuvant combination. This could help treat cancer. By combining these approaches, a greater ability to enhance personalized immune responses and achieve better therapeutic outcomes can be realized. It has been shown that nanoadjuvants can work in conjunction with modified T cells to enhance the effectiveness of cell therapies. This is achieved by reducing tumor immune inhibition and acting as immunoenhancing agents. Using such strategies, it might be possible to introduce more efficient and accurate cancer treatments that are more targeted and precise. Developing nanoadjuvants and commercializing these products is essential for establishing interdisciplinary collaborations and partnerships across universities, pharmaceutical companies, and regulatory bodies. Developing efficient and safe nanoadjuvants requires a comprehensive and coordinated approach. This combines basic, preclinical, and clinical research and helps create a coherent legal framework to ensure their safety. Additionally, increasing financial investment and focusing on production quality standards can help accelerate the entry of these technologies into the market and improve treatment outcomes for cancer patients (Table 2, Figure 2).

6. Conclusion
With the advent of nanoadjuvants, the development of cancer vaccines has made a tremendous leap forward, with promising potential to overcome some of the present limitations of immunotherapy. Nanoadjuvants enhance vaccine antigen presentation, stimulate DCs, and modulate innate and adaptive immune responses. This improves the efficacy of cancer vaccines. There is considerable evidence that these treatments improve immune responses and provide long-lasting protection. Despite this, numerous challenges remain related to their safety, large-scale manufacturing, and regulatory approvals. In conclusion, nanoadjuvants may play an essential role in developing next-generation cancer vaccines, potentially leading to improved patient outcomes and more effective cancer immunotherapies.

Ethical Considerations

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

Data availability
The datasets generated 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
Supervision: Shiva Dianaty; All authors contributed equally to the conception and design of the study, data collection and analysis, interception of the results and drafting of the manuscript. Each author approved the final version of the manuscript for submission.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgements
The authors gratefully acknowledge the support provided by the Research Deputy of Ferdowsi University of Mashhad, Mashhad, Iran, for facilitating this study. 

References

1. Feng C, Li Y, Ferdows BE, Patel DN, Ouyang J, Tang Z, et al. Emerging vaccine nanotechnology: From defense against infection to sniping cancer. Acta Pharm Sin B. 2022; 12(5):2206-23. [DOI:10.1016/j.apsb.2021.12.021] [PMID]
2. Hosseini AM, Dianaty S, Shahhosseini S, Biglarifard R, Razmi R, Komeili N, et al. Advances in nanotechnology for enhanced leukemia therapy: A systematic review of in vivo studies. J Lab Anim Res. 2023; 2(6):86-99. [DOI:10.58803/jlar.v2i6.34]
3. Soleymani N, Sadr S, Santucciu C, Dianaty S, Lotfalizadeh N, Hajjafari A, et al. Unveiling Novel Insights in Helminth Proteomics: Advancements, Applications, and Implications for Parasitology and Beyond. Biologics. 2024; 4(3):314-44. [DOI:10.3390/biologics4030020]
4. Xie X, Song T, Feng Y, Zhang H, Yang G, Wu C, et al. Nanotechnology-based multifunctional vaccines for cancer immunotherapy. Chem Eng J. 2022; 437(2):135505. [DOI:10.1016/j.cej.2022.135505]
5. He R, Zang J, Zhao Y, Dong H, Li Y. Nanotechnology-based approaches to promote lymph node targeted delivery of cancer vaccines. ACS Biomater Sci Eng. 2022; 8(2):406-23. [DOI:10.1021/acsbiomaterials.1c01274][PMID]
6. Guo J, Tang L, Li K, Ma Q, Luo S, Cheng R, et al. Application of nanotechnology in therapeutic cancer vaccines. Adv NanoBiomed Res 2023; 3(7):2200122. [DOI:10.1002/anbr.202200122]
7. Kemp JA, Kwon YJ. Cancer nanotechnology: Current status and perspectives. Nano Converg. 2021; 8(1):34. [DOI:10.1186/s40580-021-00282-7][PMID]
8. Zhou J, Kroll AV, Holay M, Fang RH, Zhang L. Biomimetic nanotechnology toward personalized vaccines. Adv Mater. 2020; 32(13):e1901255. [DOI:10.1002/adma.201901255][PMID]
9. Hajjafari A, Sadr S, Rahdar A, Bayat M, Lotfalizadeh N, Dianaty S, et al. Exploring the integration of nanotechnology in the development and application of biosensors for enhanced detection and monitoring of colorectal cancer. Inorg Chem Commun. 2024; 164:112409. [DOI:10.1016/j.inoche.2024.112409]
10. Bockamp E, Rosigkeit S, Siegl D, Schuppan D. Nano-enhanced cancer immunotherapy: Immunology encounters n Cells. 2020; 9(9):2102. [DOI:10.3390/cells9092102][PMID]
11. Ren H, Jia W, Xie Y, Yu M, Chen Y. Adjuvant physiochemistry and advanced nanotechnology for vaccine development. Chem Soc Rev. 2023; 52(15):5172-254. [DOI:10.1039/D2CS00848C][PMID]
12. Liu G, Zhu M, Zhao X, Nie G. Nanotechnology-empowered vaccine delivery for enhancing CD8+ T cells-mediated cellular immunity. Adv Drug Deliv Rev. 2021; 176:113889. [DOI:10.1016/j.addr.2021.113889][PMID]
13. Akkın S, Varan G, Bilensoy E. A review on cancer immunotherapy and applications of nanotechnology to chemoimmunotherapy of different cancers. Molecules. 2021; 26(11):3382.[DOI:10.3390/molecules26113382][PMID]
14. Chen Y. Nanotechnology for next-generation cancer immunotherapy: State of the art and future perspectives. J Control Release. 2023; 356:14-25. [DOI:10.1016/j.jconrel.2023.02.016][PMID]
15. Gao S, Yang X, Xu J, Qiu N, Zhai G. Nanotechnology for boosting cancer immunotherapy and remodeling tumor microenvironment: The horizons in cancer treatment. ACS Nano. 2021; 15(8):12567-603. [DOI:10.1021/acsnano.1c02103][PMID]
16. Chauhan DS, Dhasmana A, Laskar P, Prasad R, Jain NK, Srivastava R, et al. Nanotechnology synergized immunoengineering for cancer. Eur J Pharm Biopharm. 2021; 163:72-101. [DOI:10.1016/j.ejp2021.03.010][PMID]
17. Chen S, Huang X, Xue Y, Álvarez-Benedicto E, Shi Y, Chen W, et al. Nanotechnology-based mRNA vaccines. Nat Rev Methods Primers. 2023; 3(1):63. [DOI:10.1038/s43586-023-00246-7][PMID]
18. Zhao Y, Bilal M, Qindeel M, Khan MI, Dhama K, Iqbal HM. Nanotechnology-based immunotherapies to combat cancer metastasis. Mol Biol Rep. 2021; 48(9):6563-80. [DOI:10.1007/s11033-021-06660-y][PMID]
19. Koyande NP, Srivastava R, Padmakumar A, Rengan AK. Advances in nanotechnology for cancer immunoprevention and immunotherapy: A review. Vaccines. 2022; 10(10):1727. [DOI:10.3390/vaccines10101727][PMID]
20. Davodabadi F, Sarhadi M, Arabpour J, Sargazi S, Rahdar A, Díez-Pascual AM. Breast cancer vaccines: New insights into immunomodulatory and nano-therapeutic approa J Control Release. 2022 ;349:844-75. [DOI:10.1016/j.jconrel.2022.07.036][PMID]
21. Lin YX, Wang Y, Blake S, Yu M, Mei L, Wang H, et al. RNA Nanotechnology-Mediated Cancer Immunotherapy. Theranostics. 2020; 10(1):281-99. [DOI:10.7150/thno.35568][PMID]
22. Zhou X, Lian H, Li H, Fan M, Xu W, Jin Y. Nanotechnology in cervical cancer immunotherapy: Therapeutic vaccines and adoptive cell therapy. Front Pharmacol. 2022; 13:1065793. [DOI:10.3389/fphar.2022.1065793][PMID]
23. Li Y, Miao W, He D, Wang S, Lou J, Jiang Y, et al. Recent progress on immunotherapy for breast cancer: tumor microenvironment, nanotechnology and more. Front Bioeng Biotechnol. 2021; 9:680315. [DOI:10.3389/fbioe.2021.680315][PMID]
24. Zhang H, Xia X. RNA cancer vaccines: Developing mRNA nanovaccine with self-adjuvant property for cancer immunotherapy. Hum Vaccin Immunother. 2021; 17(9):2995-8. [DOI:10.1080/21645515.2021.1921524][PMID]
25. Assis BRD, da Silva CD, Santiago MG, Ferreira LAM, Goulart GAC. Nanotechnology in adjuvants and vaccine development: What should we know? Nanomedicine (Lond). 2021; 16(29):2565-8. [DOI:10.2217/nnm-2021-0360][PMID]
26. Feng C, Tan P, Nie G, Zhu M. Biomimetic and bioinspired nano‐platforms for cancer vaccine development. Exploration (Beijing). 2023; 3(3):20210263. [DOI:10.1002/EXP.20210263][PMID]
27. Ahmad MZ, Ahmad J, Haque A, Alasmary MY, Abdel-Wahab BA, Akhter S. Emerging advances in synthetic cancer nano-vaccines: Opportunities and challenges. Expert Rev Vaccines. 2020; 19(11):1053-71. [DOI:10.1080/14760584.2020.1858058][PMID]
28. Liu J, Miao L, Sui J, Hao Y, Huang G. Nanoparticle cancer vaccines: Design considerations and recent advances. Asian J Pharm Sci. 2020; 15(5):576-90. [DOI:10.1016/j.ajps.2019.10.006][PMID]
29. Beg S, Alharbi KS, Alruwaili NK, Alotaibi NH, Almalki WH, Alenezi SK, et al. Nanotherapeutic systems for delivering cancer vaccines: Recent advances. Nanomedicine (Lond). 2020; 15(15):1527-37. [DOI:10.2217/nnm-2020-0046][PMID]
30. Qian C, Yang LJ, Cui H. Recent Advances in Nanotechnology for Dendritic Cell-Based Imm Front Pharmacol. 2020; 11:960. [DOI:10.3389/fphar.2020.00960][PMID]
31. Chatzikleanthous D, Schmidt ST, Buffi G, Paciello I, Cunliffe R, Carboni F, et al. Design of a novel vaccine nanotechnology-based delivery system comprising CpGODN-protein conjugate anchored to liposomes. J Control Release. 2020; 323:125137. [DOI:10.1016/j.jconrel.2020.04.001][PMID]
32. Hashemi Goradel N, Nemati M, Bakhshandeh A, Arashkia A, Negahdari B. Nanovaccines for cancer immunotherapy: Focusing on complex formation between adjuvant and antigen. Int Immunopharmacol. 2023; 117:109887. [DOI:10.1016/j.intimp.2023.109887][PMID]
33. Aikins ME, Xu C, Moon JJ. Engineered nanoparticles for cancer vaccination and immunotherapy. Acc Chem Res. 2020; 53(10):2094-105. [DOI:10.1021/acs.accou0c00456][PMID]
34. Zeng H, Li J, Hou K, Wu Y, Chen H, Ning Z. Melanoma and nanotechnology-based treatment. Front Oncol. 2022; 12:858185. [DOI:10.3389/fonc.2022.858185][PMID]
35. Wu Y, Zhang Z, Wei Y, Qian Z, Wei X. Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives. Chin Chem Lett. 2023; 34(8):108098. [DOI:10.1016/j.cclet.2022.108098]
36. Fang X, Lan H, Jin K, Gong D, Qian J. Nanovaccines for cancer prevention and immunotherapy: An update review. Cancers. 2022; 14(16):3842. [DOI:10.3390/cancers14163842][PMID]
37. Peres C, Matos AI, Moura LI, Acurcio RC, Carreira B, Pozzi S, et al. Preclinical models and technologies to advance nanovaccine development. Adv Drug Deliv Rev. 2021; 172:148-82. [DOI:10.1016/j.addr.2021.03.001][PMID]
38. Fontana F, Figueiredo P, Santos HA. Advanced nanovaccines for immunotherapy applications: From concept to animal tests. In: Cui W, Zhao X, editors. Theranostic bionanomaterials. Amsterdam: Elsevier; 2019. [DOI:10.1016/B978-0-12-815341-3.00010-9]
39. Liao Z, Huang J, Lo PC, Lovell JF, Jin H, Yang K. Self-adjuvanting cancer nanovaccines. J Nanobiotechnology. 2022; (1):345. [DOI:10.1186/s12951-022-01545-z][PMID]
40. Terán-Navarro H, Calderon-Gonzalez R, Salcines-Cuevas D, García I, Marradi M, Freire J, et al. Pre-clinical development of Listeria-based nanovaccines as immunotherapies for solid tumours: insights from melanoma. Oncoimmunology. 2019; 8(2):e1541534. [DOI:10.1080/2162402X.2018.1541534][PMID]
41. Kang T, Huang Y, Zhu Q, Cheng H, Pei Y, Feng J, et al. Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immune-stimulatory modality. Biomaterials. 2018; 164:80-97. [DOI:10.1016/j.biomaterials.2018.02.033][PMID]
42. Gurunathan S, Thangaraj P, Wang L, Cao Q, Kim JH. Nanovaccines: An effective therapeutic approach for cancer therapy. Biomed Pharmacother. 2024; 170:115992. [DOI:10.1016/j.biopha.2023.115992][PMID]
43. Xia J, Miao Y, Wang X, Huang X, Dai J. Recent progress of dendritic cell-derived exosomes (Dex) as an anti-cancer nanovaccine. Biomed Pharmacother. 2022; 152:113250.[DOI:10.1016/j.biopha.2022.113250][PMID]
44. Zhang L, Zhao W, Huang J, Li F, Sheng J, Song H, et al. Development of a dendritic cell/tumor cell fusion cell membrane nano-vaccine for the treatment of ovarian cancer. Front Immunol. 2022; 13:828263. [DOI:10.3389/fimmu.2022.828263][PMID]
45. Mohsen MO, Vogel M, Riether C, Muller J, Salatino S, Ternette N, et al. Targeting mutated plus germline epitopes confers pre-clinical efficacy of an instantly formulated cancer nano-vaccine. Front Immunol. 2019; 10:1015. [DOI:10.3389/fimmu.2019.01015][PMID]
46. Qin L, Zhang H, Zhou Y, Umeshappa CS, Gao H. Nanovaccine‐based strategies to overcome challenges in the whole vaccination cascade for tumor immunotherapy. Small. 2021; 17(28):2006000. [DOI:10.1002/smll.202006000][PMID]
47. Zhang J, Fan J, Skwarczynski M, Stephenson RJ, Toth I, Hussein WM. Peptide-based nanovaccines in the treatment of cervical cancer: A review of recent a Int J Nanomedicine. 2022; 17:869-900. [DOI:10.2147/IJN.S269986][PMID]
48. Mamuti M, Chen W, Jiang X. Nanotechnology‐Assisted Immunoengineering for Cancer Vaccines. Adv NanoBiomed Res. 2023; 3(1):2200080. [DOI:10.1002/anbr.202200080]
49. Chen K, Wu Z, Zang M, Wang C, Wang Y, Wang D, et al. Immunization with glypican-3 nanovaccine containing TLR7 agonist prevents the development of carcinogen-induced precancerous hepatic lesions to cancer in a murine model. Am J Transl Res. 2018; 10(6):1736-49. [PMID]
50. Meng Z, Zhang Y, Zhou X, Ji J, Liu Z. Nanovaccines with cell-derived components for cancer immunotherapy. Adv Drug Deliv Rev. 2022; 182:114107. [DOI:10.1016/j.addr.2021.114107][PMID]