Updates on cancer vaccines in brain cancer: Advances in neuroblastoma, delivery systems, and emerging technologies

ABSTRACT

Neuroblastoma stands as a major concern in pediatric oncology because it develops from neural crest cells as a neuroendocrine cancer. Nanoparticle-based vaccine delivery approaches the therapeutic activity of immune cells only toward tumor cells without inflicting damage to healthy tissues like those sustained by chemotherapy and radiation therapy. Neuroblastoma treatment faces two major barriers: penetrating the blood–brain barrier (BBB) and using nanoparticle technology. The promising developments for neuroblastoma treatment emerge from mRNA COVID-19 vaccine research and brain cancer vaccine clinical trials especially through phase I autologous dendritic cell vaccine studies. Future research needs to develop optimized nanoparticles which can trigger the release of mRNA or peptides based on tumor-specific pH and enzyme signals. The BBB can be opened temporarily through ultrasound and receptor-mediated transport approaches, which enhance vaccine delivery to brain tissues. New immunotherapeutic approaches for pediatric malignancies emerge from these recent findings to yield future success.

Introduction

Brain cancer is one of the most difficult types of malignancy, contributing to increased morbidity and mortality rates. According to the most current statistics, primary brain and CNS tumors account for 1.4% of all cancer deaths worldwide, and glioblastomas are the most frequent and malignant form of the disease in adults.¹ However, neuroblastoma, a neuroendocrine tumor derived from neural crest cells, is a significant problem in pediatric oncology. While being discovered more often outside the head, it metastasizes to the CNS constantly so that in the late stages, brain-directed therapies are deemed indispensable.² This highly aggressive, albeit quite rare, childhood neoplasm is responsible for approximately 15% of mortalities due to cancer in children under the age of 5, in this regard, attempting novel therapeutic strategies.^3,4 A major limitation encountered in managing brain cancer, including neuroblastoma, is the blood–brain barrier (BBB). The BBB is a shielded, tight layer that concerns the control of the exchanges across the blood–brain barrier. It plays a vital function in regulating CNS homeostasis; nonetheless, it obstructs the effectiveness of many therapeutic drugs by restricting their penetration into the brain.^5,6 This protective mechanism constitutes a major challenge to cancer treatment delivery, especially drugs that can be identified as large molecules, including antibodies, nanoparticles, or nucleic acids. Hence, techniques to cross or avoid the BBB form a crucial part of the treatments of brain cancers for which immunotherapy, including vaccines, is still in its exploration stage, as explored by.⁷

There is potential in cancer vaccines as a therapy for brain cancer because they are known to encourage the immune response of specific characters. Unlike chemotherapy, radiotherapy, and other conventional treatments that exert great toil on healthy cells of the body, vaccines work in a way that they seek to address the body’s immune response to focus on the extermination of tumor cells.^8,9 These vaccines put tumor-associated antigens or neo-antigens into display, which elicit an immune response that may result in tumor eradication or relapse prevention. There has been much interest in brain cancer vaccines as these vaccines can help overcome many of the barriers imposed by traditional therapies for specific cancers such as glioblastoma.^10,11 As promising as they may be, there are certain problems associated with the clinical application of cancer vaccines in brain tumors. One significant limitation is the immunosuppressive character of the brain along with the BBB. This poses a challenge in accessing and treating tumors through immune cells or vaccine components.¹² However, the improved technology of vaccine delivery systems that have emerged from nanoparticles and mRNA technology offers some cues to overcome these barriers.¹³ In addition, while early-stage clinical trials have shown similar effectiveness, further and more comprehensive brain cancer vaccine formulation trials should be conducted on large populations. A comprehensive understanding of technology advance and progresses on neuroblastoma will benefit therapeutic delivery. Therefore, this review focus on the current update on therapeutics challenges in managing neuroblastoma, specifically overcoming the BBB and application of nanoparticles technology for vaccine delivery.

Neuroblastoma: focus and challenges

Neuroblastoma is a type of cancer particularly found in children originating from neuroblasts or the cells in the development of the sympathetic nervous system, as shown in Figure 1. It mostly occurs in children under the age of 5 years, and as a clinical entity, it can be a single tumor mass or disseminated metastases. The disease stages are differentiated based on the International Neuroblastoma Staging System (INSS), Stage 1, which means a localized disease that can be surgically removed, to stage 4, in which cancer cells spread to other unrelated organs.^14,15 Neuroblastoma has an overall five-year survival percentage, which is different in both Stages and ages of diagnosis. For instance, children diagnosed with localized neuroblastoma have a chance of 90% surviving, whereas, for patients with stage 4 neuroblastoma, the survival rate is much lower, ranging between 40% and 50%.^14,16

Figure 1.

Process of Oncolytic virotherapy for neuroblastoma.

Treatment in neuroblastoma has always involved treatment such as surgery, chemotherapy, as well as radiotherapy. Nevertheless, these approaches are related to significant toxicity and cause far-reaching consequences in children.^17,18 There has been a growing focal point toward new immunotherapies like monoclonal antibodies, target therapies, and cancer vaccines that have been shown to enhance results without side effects. These new treatments have been suggested in clinical research, and there is evidence regarding improvement in survival and low repetition.^18,19

Using vaccines for the treatment of kindness is quite appealing generally when directed toward neuroblastoma, given all the issues associated with this form of cancer, not the least of which are specific to pediatric patients. This justifies their focus, given that vaccines have a strong potential for generating an armed immune response against the antigen-presenting tumor cells without inflammation, commonly observed in conventional therapies.^9,20 Tumor-associated antigens (TAAs) are common in neuroblastoma tumors, including GD2, a disialoganglioside known to be over-expressed on neuroblastoma cells. These antigens are ideal vaccine targets and help to cause a powerful immune response, thus making them suitable for immunotherapy, according to.²¹

Nevertheless, there are some significant obstacles toward activating vaccine strategies in neuroblastoma. They described how the anti-immune tumor micro-environment may interfere with immune actions. Furthermore, the differences in immunity and developmental levels across different age groups may explain why vaccines may not work as expected in young children.²² Thus, studying the characteristics of the micro-environment of the tumor, finding out which antigens should be used as the main ones in the anticancer vaccine, and choosing the right ways of immunoassay administration are the most important issues which can help in increasing the immunological effectiveness of the vaccine in question, used for treating neuroblastoma. Thus, though the potential of cancer vaccines in eradicating neuroblastoma is quite tempting, the experts in the field require more understanding of tumor biology, patient characteristics, and immune context to create an efficient immunotherapeutic approach.

Overcoming the blood–brain barrier for vaccine delivery

The blood–brain barrier (BBB) is a highly developed and biologically active structure primarily consisting of layers formed by endothelial cells of the cerebral capillaries. These cells are highly joined by tight junctions, which greatly limit paracellular transport and regulate the balance of the CNS.²³ The BBB acts as a filter, allowing only the beneficial particles, such as nutrients and small molecules, while keeping out anything that is not beneficial into the brain. However, this protective role presents major hurdles in distributing therapeutic agents, including vaccines, which typically have difficulties crossing this barrier.²⁴

Drug and vaccine access barriers to the brain are the formation of the BSCB characterized by high technical resistance, efflux transporters (P-glycoprotein), and a dense extracellular matrix that reduces access to substances to cells.²⁵ As a result, most therapeutic agents fail to achieve their target site with therapeutic concentrations, accumulating minimal therapeutic effects. A detailed knowledge of the BBB organization and its functions is crucial to designing efficient approaches to improve the delivery of vaccines that can target such brain tumors as neuroblastoma.

Many approaches have been proposed to open or to transiently compromise the BBB to allow the entry of vaccines and therapeutic drugs into the brain. One strategy is based on applying nanoparticles that can protect vaccines and facilitate their penetration into the CNS crossing BBB using several pathways: receptor-mediated endocytosis and transcytosis.²³ The nanoparticles can be designed to selectively bind to receptors on the endothelial cells of the BBB and release the vaccine within the CNS.

Another technique that has significant potential is the combined use of focused ultrasound (FUS) and microbubbles. This method makes it possible to open the BBB locally and temporarily, allowing it to deliver big molecules, including vaccines, into the brain parenchyma.²⁶ Ultrasound waves are then applied at the desired site to cause mechanical agitation by microbubbles in which the tight junctions of the BBB are broken to improve permeability while invasiveness is still low. Opening the blood–brain barrier (BBB) with FUS is a very effective technique to get mRNA- or peptide-based vaccinations into the central nervous system. However, this method has some safety risks that need to be handled cautiously.

Strategies for reducing risk and improving performance

1. Parameter titration: Keeping the peak negative pressure/MI below ~0.25 MPa and employing smaller MBs ( <2 µm) reduces sterile inflammation and microbleeds while keeping permeability.²⁷

2. Real-time cavitation feedback: Closed-loop acoustic-emissions controllers change the millisecond power to keep the system in the “stable cavitation” window. If they detect inertial events, they stop sonication.²⁸

3. Microbubble dose scheduling: Lower MB volume doses ( <4 µL kg⁻¹) or fractionated injections alleviate vascular stress without diminishing medication absorption.²⁷

4. MRI or ultrasound guiding with heat maps: Imaging ensures that the target is focused, confirms that the BBB is closed, and finds asymptomatic edema early.

5. Peri-procedural pharmacology: Short doses of dexamethasone or NSAIDs have been suggested to mitigate cytokine peaks; experimental studies with CSF-1 R inhibitors indicate that concurrent myeloid regulation may further attenuate neuroinflammation²⁹ Table 1.

6. Session spacing: Clinical series with 4- to 6-week intervals facilitate microvascular repair and demonstrate no cumulative cognitive loss after more than ten openings.³¹

Table 1.

Principal for overcoming safety risks associated with FUS-mediated BBB opening.

Risk category	Mechanistic basis	Representative evidence
Sterile neuro-inflammation	Acoustic cavitation and vessel stretch trigger the release of danger-associated molecular patterns, glial activation, and transient cytokine surges (IL-1β, TNF-α).	Kovacs et al. showed that FUS + microbubbles (MB) produced a self-limited inflammatory transcriptome and microglial recruitment in mice.29
Micro-hemorrhage and edema	Excess pressure or large MB diameter causes inertial cavitation, tearing micro-vessels and red-blood-cell extravasation.	A 2024 mouse study found that rising MB dose increased pro-inflammatory markers and petechiae area in a pressure-dependent manner.27
Off-target or systemic immune activation	BBB opening can let peripheral immune cells and antibodies enter parenchyma; FUS itself up-regulates PD-L1 and other checkpoints in tumor models.	MR-guided FUS in glioma patients raised checkpoint‐related transcripts in sonicated tissue.30
Cumulative effects of repeat sessions	Re-opening the BBB could create chronic low-grade inflammation or cognitive change if parameters are not optimized.	A phase-I glioblastoma trial using monthly pulsed ultrasound openings reported only Grade 1–2 headaches and no neuro-deficits, supporting safety with monitored dosing.31

When these precautions are taken together, multi-center Alzheimer’s and glioblastoma trials have now completed hundreds of FUS-BBB sessions with only temporary headaches and changes in MRI T2*—suggesting that the technology can be made safe enough for vaccine delivery if strict adherence to parameters and close monitoring are followed.

Furthermore, new approaches like the application of mRNA vaccines open up new possibilities for overcoming the obstacles of BBB. According to some studies, mRNA vaccines’ small size and lipid nanoparticle-based nature can be tweaked to cross the BBB and provoke strong immunity within the CNS.³² Such strategies suggest that improving the effectiveness of vaccines specific to neuroblastoma or other brain tumors is possible.

Immunotherapy can be described as a new approach to tackling the issue brought by the BBB in brain cancer treatment. Since the immune system is selective for tumor cells, some immunotherapeutic agents can increase BBB permeability selectively as seen in Figure 2. For example, immune checkpoint inhibitors and CAR T cell therapies have been tested to alter the immunobiology within the brain and thus affect the barrier between the CNS and blood.

Figure 2.

New development in nanocarrier drug delivery technology that crosses the blood–brain barrier.

Furthermore, the intervention through vaccine-induced immune activation may increase cytokine and chemokine concentrations, which disrupts the BBB and enhances the penetration of other therapeutic agents in CNS.³³ These immunotherapeutic approaches do not only improve the targeted delivery of vaccines but also possibly the therapeutic dose of brain tumors such as neuroblastoma.

Therefore, more challenges make BBB a barrier to the success of vaccines in brain cancer therapy; however, continuous study and work to develop new ideas and immunotherapeutic interventions show that improvements in this area are possible.

Nanoparticles as a vaccine delivery system

In the recent past, the field of medicine has been noted to benefit greatly from nanoparticles considering drug and vaccine delivery systems. These particles, which range in size from 1 to 100 nm, can be synthesized from lipids, polymers, metals, or silica; these tiny particles possess novel physical and chemical characteristics that augment therapeutic benefits.^34,35

Nanoparticles employed in cancer therapy are liposomes, dendrimers, polymeric nanoparticles, and inorganic nanoparticles such as gold or silica nanoparticles. For instance, liposomes are biodegradable and good at loading both water-soluble and lipophilic drugs, and polymeric nanoparticles can improve the release profile and have better stability.³⁶ By virtue of their characteristics, nanoparticles enable better dissolution, delivery to the required area, and limited general toxicity compared to normal particulate systems and, hence, are ideal for combating difficult diseases like brain cancer.

Nanoparticles have many benefits when treating brain cancer, such as better penetration through the blood–brain barrier (BBB) than other conventional therapeutic agents. In addition, nanoparticles can be engineered to optimize biodistribution, increase cellular delivery of drugs, and augment tumor-associated antigen immunotherapy for better patient benefits.^37,38 Studies have shown that nanoparticles’ ability to transport across the BBB and discriminating delivery to neuroblastoma hinges on three tightly interrelated physicochemical parameters such as size, surface charge, and surface ligands while conquering off-target uptake.^27,39 The hydrodynamic diameter or size of 10–60 nm particles exploit receptor‐ or adsorptive-mediated transcytosis more efficiently than larger systems and can still accommodate therapeutic payloads. The pre-clinical models of²⁷ showed that about 25 nm ligand-free mesoporous silica NPs achieved a 15-fold higher brain penetration than 100 nm analogues. Also, the study of³⁹ indicated that a sub-30 nm gold nanocluster functionalized for high-risk neuroblastoma successfully crosses the BBB and induces ferroptotic death in MYCN-amplified cells. However, identical clusters aggregated to >80 nm lost both permeability and specificity. Surface charge (ζ-potential) that are mildly cationic (≈+5 to +15 mV) or near-neutral coatings enhance electrostatic interactions with brain endothelial cells’ negatively charged glycocalyx without substantial serum-protein adsorption or complement activation.⁴⁰ Strong anionic systems resist positively charged particles (>+25 mV), which have increased cytotoxicity and faster clearance. Exploring these charge-switching designs, such as PEG-shielded NPs, effectively reduces systemic “stickiness” and restores BBB transport in brain capillaries.⁴¹ Again, ligand modification enhances gaining entry. Therefore, adorning nanoparticles with transferrin, lactoferrin, angiopep-2, or P-selectin ligands harnesses numerous receptor-mediated transcytosis pathways on BBB endothelium, hence enhancing brain inflow three- to ten-fold over non-targeted controls.⁴² The dual functionalization of nanoparticles with a BBB ligand plus a neuroblastoma marker (e.g., anti-GD2, ALK-aptamer, GPC2 peptide) provides two consecutive specificity filters. For example, localized almost entirely to GD2+ xenografts with minimal absorption in GD2- organs, multifunctional anti-GD2 iron-oxide nanoparticle.⁴³ Furthermore, integrating these physicochemical characteristics and optimization strategies for minimal off-target effects are highlighted in Table 2, including the design, functional strategies, and their benefit.

Table 2.

Optimization strategies for minimal off-target effects.

References	Design	Functional strategies	Benefit
40	Precision sizing	Controlled microfluidic or flash-nanoprecipitation to hold diameters ≤60 nm with narrow PDI	Maintains transcytosis competency and uniform biodistribution
41	Stealth/charge modulation	pH-responsive zwitterionic or PEG shells that mask surface charge in blood but deshield in the acidic tumour niche	Reduces opsonization and liver uptake; restores positive charge for tumour penetration
42	Dual-target ligand density	Sparse (1–5%) BBB ligands + dense (10–20%) GD2 ligands; validated by SPR or MD simulation	Balances endothelial binding with high-affinity neuroblastoma recognition, avoiding endothelial “trapping.”
43	Biomimetic coatings	Macrophage- or exosome-membrane cloaks that naturally express integrins and CD47	Exploit endogenous BBB migration cues and confer “don’t-eat-me” signals to phagocytes.
40	Stimuli-responsive cores	pH-/ROS-cleavable linkers or magnetic/ultrasound-triggered release	Adds a third level of spatial control, ensuring the drug unloads only within tumour parenchyma
42	Transient BBB modulation	Low-intensity focused ultrasound or P-selectin-targeted nanocarriers to open tight junctions locally.	Allows pulse dosing with minimal systemic permeability changes

Cancer vaccines have undergone a tremendous change through nanoparticle-based delivery systems, improving their targeting efficiency and immune response. Such systems can encapsulate antigens, adjuvants, and other immunomodulatory agents and enhance their stability in controlled releases at the target site.^9,44

The effectiveness of nanoparticle platforms for developing a vaccine involves increasing antigen presentation, activating dendritic cells, and induction of comprehensive T-cell activation. For example, nanoparticles may be engineered to bear a structure–activity relationship mimicking that of PAMPs in immune involvement and activation.³⁸ Additionally, nanoparticles’ size and surface properties can be tuned to facilitate optimal interactions with immune cells, resulting in enhanced uptake and processing of the vaccine components.

Recent years of nanoparticle system development have typically generated nanoparticles that can carry multiple agents at once or use multiple therapies concurrently. For example, pH-sensitive nanoparticles, which are designed to release their contents in the tumor microenvironment that is generally more acidic than normal, are an active area of research, as is the use of targeted nanoparticles that use ligands for cell targeting.⁴⁴ These advancements are helping to shape a new precise immunological defense mechanism against the attack of brain cancer such as neuroblastoma. Furthermore, neuroblastoma tumors exhibit significant heterogeneity and are generally “cold,” characterized by a scarcity of effector T cells and a predominance of M2-polarized tumor-associated macrophages (TAMs), myeloid-derived suppressor cells, and TGF-β-rich stroma that inhibit cytotoxic immunity.⁴⁵ Therefore, a successful therapeutic vaccine must first stimulate professional antigen-presenting cells (APCs), secondly, ensure extensive antigen coverage to address intra-tumor heterogeneity, and thirdly, restructure the myeloid-dominant microenvironment to facilitate the survival and function of entering T cells. This review suggests that optimization strategies, including dual-target constructs, attach a BBB-crossing peptide (like angiopep-2) to tumor antigens to improve lymph-node trafficking and cross-priming before cells meet the suppressive TME. Spatiotemporal adjuvant release: load TLR/STING agonists into pH-responsive nanoparticles to keep innate activation only on the tumor bed and stop systemic cytokine surge. Scheduling for TAM depletion and reeducation: Give CSF-1 R or IDO inhibitors 24–48 h before immunization so the TME is ready when effector T cells enter. Low-dose radiation or concentrated ultrasonic “priming” temporarily raises chemokines (CXCL9/10) and vascular adhesion molecules, which enhances T-cell infiltration without broad myeloablation, as detailed in Table 3.

Table 3.

Designing vaccines to surmount immunosuppression.

Barrier in the NB-TME	Vaccine-design lever	Scientific evidence
Low APC activation and limited type-I IFN	Combinatorial adjuvants (e.g., CpG-K3 + STING agonist c-di-AMP) that synchronously engage TLR9 and STING pathways, licensing dendritic cells and boosting neo-epitope–specific CD8+ responses ten-fold	CpG + STING formulation drove dense CD8+ infiltration and synergized with anti-PD-1 in murine NB models.46
Antigenic heterogeneity	Multi-epitope or mRNA platforms that encode GD2, PHOX2B and individual neo-antigens in a single construct	In pre-clinical studies, mRNA vaccine blueprints for high-risk NB demonstrate robust, multi-antigen T-cell priming.47
Immunosuppressive TAM/MDSC network	Myeloid-reprogramming adjuvants (e.g., β-glucan, CSF-1R blockade) co-delivered with the vaccine.	A β-glucan + GM-CSF bivalent ganglioside vaccine now in phase II (NCT04936529) aims to convert TAMs to an M1 phenotype and improve relapse-free survival48
Checkpoint-rich stroma	Built-in or co-administered ICB (e.g., anti-PD-1 ± CTLA-4)	Ongoing phase I GVAX/GM-CSF vaccine plus nivolumab/ipilimumab (NCT04239040) is reporting increased CD8+/Treg ratios in tumour biopsies49

Some case studies and clinical trials have revealed that nanoparticle systems have great prospects in vaccine delivery for brain cancer. An example includes gold nanoparticles functionalized with tumor-associated antigens to improve immune reactions against glioblastoma.^9,23 In various in vitro and in vivo studies, these nanoparticles were characterized by appreciable tumor regression and improved overall survival in animal models, suggesting their applicability in clinical practice.

Other opportunities include engineering polymeric nanoparticles designed to encapsulate mRNA-based vaccines with potential applications for neuroblastoma therapy. Other clinical trial studies also revealed that these mRNA nanoparticles induced powerful immunogenicity and minimized tumor size in patients, thus illustrating the feasibility of mRNA nanoparticle delivery systems for brain tumors.^26,50

Lipid-based nanoparticles have also been employed for the cardinal delivery of immune checkpoint inhibitors and cancer vaccines since they are ideal for mediating immune escape in Brain tumors. Clinical studies of this treatment strategy have concluded that there are benefits, such as increased overall survival and progression-free survival among patients with resistant brain cancers.⁵¹

mRNA vaccine systems for brain cancer

mRNA vaccines are new-generation vaccines that use the body’s cellular process to create an immune response. Both mRNA-based vaccines release synthetic mRNA encoding tumor-specific antigens to force the manufacturing of the respected protein and stimulate humoral and cellular immunity.⁵² The mechanism of action is the internalization of mRNA by dendritic cells, which breaks it down into antigens and displays it on major histocompatibility complex (MHC) to T cells, allowing for selective killing of cancer cells.⁵³

The experience of creating and applying mRNA vaccines for coronavirus has shown the effectiveness of the approach in the field of cancer immunotherapy. Their versatility in design and manufacturing makes it possible to develop vaccines, particularly for an individual’s tumor antigenicity pattern.³⁶ Further, mRNA vaccines do not include the host genome upon entering it; thus, lower oncogenicity is observed than in viral vector-based vaccines.

While the general application of mRNA vaccines has only recently taken off in non-oncological contexts, particularly with the EUA granted to the Pfizer-BioNTech and Moderna COVID vaccines, there was early curiosity about their use in cancer therapy. Investigators have embarked on Phase I clinical trials of mRNA vaccines for numerous cancers, including melanoma, lung cancer, prostate cancer, and other cancers. Reports have revealed that these vaccines can stimulate particular T-cell reactions and improve the patients’ prognosis.⁵⁴ Regarding antigenic differences in most cancer types, where neuroblastoma is concerned, component differences mean that mRNA vaccine approaches work. When GD2, essentially present in neuroblastoma, is bound, these cells can be targeted through synthetic mRNA vaccines that trigger interferon-gamma production in T-cells. Preliminary investigations for the initial trials of GD2-targeted mRNA vaccine have shown positive early-phase clinical trials in patients; enhanced immune response and tumor regression were also observed in animal models.⁵¹ In addition, the ability to coordinate both the mRNA vaccine and another therapy approach, including checkpoint inhibitors and targeted therapies, could provide a more potent approach to brain cancer treatment.

However, several barriers remain concerning the effective delivery of mRNA vaccines to the brain and other body organs. Everybody feels that the coming of mRNA vaccines eliminates barriers to the treatment of diseases. The following challenges remain in the treatment using mRNA vaccines: The limitation of BBB is another challenge because it limits the access of large molecules by using nanoparticles and formulations such as mRNA in the CNS. Therefore, the search for robust strategies that can allow the transport of the mRNA vaccines across the BBB poses the most significant challenge.

Progress in mRNA delivery systems in recent years has been mostly centered on better stability, efficient uptake in target cells, and efficacy. For example, lipid nanoparticles (LNPs) have been used to deliver mRNA through packaging, protecting it from degradation and enhancing cellular uptake by the organism.⁵⁵ Moreover, structural changes to the mRNA have also been observed where the arginine-generating modified nucleotides possess increased stability and translation rates.⁵⁶

Some recent in vitro and in vivo experimental evidence indicates the general possibility of utilizing mRNA vaccines to cross the BBB. For instance, intranasal or focused ultrasounds have been used in certain studies, suggesting they could help deliver mRNA across the BBB and reach therapeutic levels in brain tissues.^34,57 That is why clinical trials should be carried out continuously to analyze the effectiveness of these novel delivery methods in patients diagnosed with brain cancer. Some formulation add-ons that may fortify LNP-mRNA vaccines for CNS tumors include Ionizable lipids with pK_a ≈ 6.2–6.5 bind and protect mRNA while in circulation, but when they enter endosomes, they protonate and break down the membrane to release the mRNA. New structure-activity screenings reveal that adding pH-responsive thiophene tails or biodegradable amide linkers to SM-102/ALC-0315 lipids makes them two to three times better at transfecting brain cells and less harmful to the liver.⁷⁰ Smart PEGylation PEG-lipids help keep colloids stable and in circulation longer, but too much PEG stops fusion. Cleavable PEG_2000-DMG or short-acyl PEG-PE that sheds within minutes after reaching brain micro-vessels recovers fusogenicity without sacrificing stealth, tripling mRNA expression in intracranial mice.⁷¹ Lipids that help and lipids that escape adding cone-shaped DOPE or cholesterol analogues raise the “critical packing parameter,” which encourages non-lamellar phases and endosomal rupture. However, less than 2% of internalized LNPs getaway. Adding endosome-destabilizing peptides or small-molecule proton sponges (such as imidazole lipids) can increase cytosolic release by as much as six times⁷². Surface stimuli target the BBB by adding transferrin, angiopep-2, or selective-organ-targeting (SORT) lipids and LNPs are moved from the liver to the brain; the key optimization strategies are detailed in Table 4. This results in five to ten times more tumor deposition in orthotopic glioma and neuroblastoma models. Composite or hybrid carriers polymer-lipid hybrids and exosome-mimetic membranes enhance mechanical stiffness and facilitate immune evasion; in mouse medulloblastoma, they extended mRNA half-life from less than 6 h to over 24 h and increased IFN-β production seven-fold.⁴²

Table 4.

Optimization and formulation add-ons that fortify LNP-mRNA vaccines for CNS tumors.

Lever	Practical tweak	Expected gain
Ionizable core	Tune pK_a & biodegradability of novel lipidoids via deep-learning design	↑ stability, ↓ toxicity
Cleavable PEG	Acid-labile or enzymatically cuttable PEG-lipids	Maintains stealth → restores fusion
Endosomal boosters	DOPE, sterol analogues, proton-sponge peptides	↑ escape fraction
BBB ligands/SORT lipids	Transferrin, angiopep-2, permanent cationic SORT additives	Redirects tropism to brain tumours
Hybrid shells	Exosome or polymer overlays	Extra nuclease protection and immune evasion

Therefore, the development of mRNA vaccine systems represents a revolution in treating brain cancer, especially neuroblastoma. However, there are concerns concerning the delivery and sustained development of anti-PD-1. Immunological perspectives are being developed with constant improvements in innovation to give a superior and focused immunotherapeutic plan.

Synergy of delivery systems: nanoparticles and mRNA

Integrating mRNA vaccine technology with nanoparticle-based delivery systems is a promising feature, especially for brain cancer immunotherapy. Lipid nanoparticles (LNPs) are one of the common formulations developed as a vaccine delivery system that protects the mRNA vaccines inside it because mRNA molecules are susceptible to nucleases in blood circulation.⁵⁸ They can be functionalized to enhance tissue selectivity depending on the surface modification or ligand conjugation to get across the BBB, for example, in cancer brain tumors.¹³

Kou et al.⁵⁹ suggested that this synergy has enhanced immunity because of the protection and controlled release of mRNA, which enhances antigen presentation and immune response activation. Furthermore, nanoparticle platforms enhance the ability of the vaccine to exist and circulate in the brain tissues – which is essential in addressing neuroblastoma and other aggressive brain cancers.

The binary combination system of nanoparticle and mRNA creates the pathway for the contextual application of brain cancer vaccines at molecular genetics and antigenic tumor levels. The application of precision medicine in cancer therapy requires first recognizing specific alterations unique to cancer cells or surrounding tissues and encoding these modifications into mRNA vaccines that stimulate an immune response.⁶⁰ Nanoparticle-based delivery systems improve this approach by reducing side effects and improving the efficiency of the applied treatment at the tumor site.

These improvements in genomic profiling and bioinformatics platforms make it possible for scientists to develop targeted mRNA vaccines for patients, depending on various characteristics of a tumor or cancer-related proteins, such as neoantigens, for example, in neuroblastoma.⁹ Apart from increasing the efficiency of an immune response to tumor cells, this approach minimizes the chances of tumor cells developing immune resistance, which opens up the possibility of designing individual vaccines for patients with glioblastoma multiforme.

Clinical progress and trials in cancer vaccines for brain cancer

In recent years, cancer vaccines have emerged as a potential modality of therapeutic intervention for neuroblastoma and other gliomas, and several phases of clinical trials are underway currently. These trials are meant to assess the safety, immunogenicity, and efficacy of different types of vaccines, namely dendritic cell vaccines, peptide vaccines, and mRNA vaccines. For instance, the phase 1 trial (NCT03275402) on autologous dendritic cell vaccines in pediatric neuroblastoma revealed promising results in the development of immune response against tumor-associated antigens.^61,62

Moreover, for glioblastoma, one of the most aggressive types of brain cancer, the vaccine mRNA-4157, along with pembrolizumab, has entered Phase II trials (NCT03897881), making it possible to hope for effective treatment by stimulating the immune response to tumor neoantigens.⁵² These trials are quite important in determining the feasibility of using vaccines in treating brain cancer, particularly neuroblastoma, because crossing the BBB and the immunosuppressive tumor micro-environment poses a challenge.

The immunogenicity and safety profiles depicted in early-stage trials have been promising, but the efficacy of the vaccine-based treatment in brain cancers is still a challenge. Perhaps, the significant challenge for developing therapeutic cancer vaccines is that tumor antigens are diverse, and sometimes, only a few representative proteins are targeted with vaccines. However, some recent trials have shown some success. For instance, in the peptide vaccine study employing the GD2 antigen in neuroblastoma, patients reported increased survival periods and slowed disease progression, but minimal remission from tumors is still visible.⁶³ It is necessary to design, manufacture, and issue personalized mRNA vaccines against neuroblastoma antigens like GD2 in a matter of weeks. However, each batch is unique, very small, and intended for a juvenile population with a rapidly progressing disease. Labor-intensive sequencing, in-vitro transcription, lipid-nanoparticle (LNP) formation, and quality control (QC) assays done from scratch for each child make it harder to scale up. A recent evaluation of production says that the end-to-end cycle still takes 4–6 weeks and costs more than $100,000 per dose, mostly because tests for identification, purity, potency, and sterility can’t be combined across batches.⁷³ Moderna’s new “digital-design/small-batch” infrastructure can make adult melanoma vaccinations in 7 days, but it still needs to be tested in real-time situations for children.⁷⁴ From a regulatory standpoint, each personalized construct is classified as a gene-therapy medicinal product within both FDA and EMA frameworks, necessitating comprehensive Chemistry-Manufacturing-Controls (CMC) dossiers, comparability plans, and pediatric-first-in-human justification.⁷⁵ Regulators have expressed flexibility, but the Lancet Oncology says that different countries’ rules for release testing and GMO supervision are already delaying first-in-human starts for adult vaccines by months. An industry survey shows that there is still much misunderstanding regarding how many “individual products” can be pooled under one license and how potency can be checked when each patient gets a different epitope set. The clinical window for neuroblastoma can close rapidly: 40% of children relapse despite anti-GD2 antibody therapy, frequently within 6 months⁷⁶—a timeframe that does not allow for much regulatory delay. Some mitigation strategies that are being looked into right now are platform master-files (a single, pre-qualified LNP excipient set), modular GMP “pods” that are located next to pediatric centers to cut down on transport time, and release-by-exception using high-throughput, digital PCR-based identity tests linked to validated in-process controls. Parallel regulatory and manufacturing workstreams, known as “rolling CMC,” and the utilization of existing pediatric gene therapy guidelines for potency, shedding, and long-term follow-up, could speed up the process while still keeping safety in mind.

Minor negative outcomes of brain cancer vaccines are usually fatigue, reaction in the areas of administration or injection, flu-like symptoms or anything close to that. However, more severe immune-related AE has been reported in some instances, especially when vaccines are given jointly with immune checkpoint inhibitors. Nevertheless, the developments persist; a new strategy revealed for further enhancements of existing techniques combines vaccines with other immunotherapies such as checkpoint inhibitors and adoptive T cell therapy. New carriers, such as nanoparticles, are being explored to improve the effectiveness of vaccines with drawbacks.

Future directions and challenges

The ability to alleviate the problem associated with crossing the blood–brain barrier (BBB) and the ability of the therapeutic agents to target the tumor cells dictate the future of brain cancer vaccines. Recent advancements in nanoparticle design, like stimuli-responsive delivery systems, also seem to enhance BBB uptake.⁹ These nanoparticles may be programmed to release their contents, for instance, mRNA or peptides, at specific stimuli such as changes in pH and the presence of enzymes in the tumor microenvironment, thus enhancing the delivery of vaccines. Other technologies, for instance, focused ultrasound and receptor-mediated transport systems, have also been discussed to temporarily break the BB and improve the absorption of the cancer vaccines in brain tissues.⁶⁴ Furthermore, sustained advancement of the mRNA delivery systems will be the key to fulfilling those goals and enabling the stable and effective retention of the vaccines once they have entered the brain. These enhanced improvements not only degrade the effectiveness of the mRNA vaccines but also reduce off-targeting, thus making the vaccines safe and efficient for use.

This next phase of brain cancer care is a timely focus on person-oriented care and combined treatments. Individualized vaccines that stimulate the tumor-associated antigenic profile are popular due to the technological benefits, high immunity, and low probability of mutational immune evasion.⁶⁵ A better understanding of tumor evolution and better matching of biomarker targeting results in machine learning algorithms will enhance the prospects of cancer vaccine modification in response to cancer development and its treatment.

However, the plan to use vaccines with other immunotherapies, like immune checkpoint inhibitors or CAR-T cell therapies, reveals a highly synergistic form of treatment strategy that may well do away with the immunosuppressive nature of brain tumors.^66,67 Initial clinical tests of combination therapies have revealed certain advantages, as tumor destruction is known to increase and the rates of patients’ survival improve. This sounds like the future of treatment in cancers affecting the brain, such as neuroblastoma, using a combination of vaccines, avoiding the checkpoint, and biopsy assaying other therapies.

The use of new vaccine therapies for brain cancer also presents major regulatory and ethical concerns, as well as the creation of new vaccines. It is uncommon for regulatory approval of innovative products that use new techniques not previously used in vaccines or therapeutics, such as the mRNA vaccines and nanoparticle-based deliveries, to take time. Organizations like the US FDA and the European Union’s EMA demand complete data from pre-clinical and clinical trials for these treatments. Furthermore, other forms of authorization, such as the fast-track approval processes, may be needed for patients with progressive, refractory cancers, but this must be done on a case-by-case basis and assessment of the risk/benefit ratio of such an action.^36,67

Ethically, there are drawbacks when it comes to access to those treatments since some therapies only require modern and advanced equipment, which are very expensive and sometimes unavailable in the developing world. In addition, as the biosphere moves toward personalized vaccines, other issues such as data protection, consent, and equality in access to personal medicine will also arise. These challenges will have to be overcome in order for new brain cancer vaccines to be safe, effective, and affordable for all patients.

Therefore, there are numerous challenges; although we have focused only on a few that must be conquered, the future of brain tumor vaccines is bright due to advanced technologies and the integration of vaccinations with other targeted therapies. In future, as more collaboration comes into play and regulatory and ethical issues are worked out, vaccine-based therapies will likely become one of the main tools in battling brain cancer.

Conclusion

The use of vaccines with cancer for the treatment of brain cancer, especially neuroblastoma, has surmounted many improvements in recent years. New strategies like the nanoparticle-mediated drug delivery system and mRNA vaccine platform have emerged as potential ways to enhance immunotherapy in brain tumors and cross the BBB. These are significant in countering some obstacles that have beset prior therapies due to the neuroprotective attribute of the BBB and the immunosuppressive nature of the tumor mass microenvironment. From improved stability, targeting and penetration, nanoparticles as rich carriers have brought innovation to the vaccine delivery method. Thus, the results of mRNA system application in other cancers may indicate its applicability to treating brain cancer using advanced delivery strategies and an individual approach.

Consequently, advancing cancer vaccines combined with modern technologies is expected to bring about remarkable changes in brain cancer. Further work should aim at improving delivery systems, for example, the conjugation of nanoparticles with mRNA vaccines to improve the stability of the vaccines, as well as accuracy and effectivity in activating immune responses. Furthermore, although monoclonal antibodies work well to treat certain cancers, developing individual cancer vaccines for patients based on their tumor gene and antigen characteristics could result in better and longer-lasting treatment outcomes that could extend patient’s life and enhance their quality of life.

Therefore, investigating combination therapies, where vaccines are combined with checkpoint inhibitors or other immunotherapies, may improve outcomes of patients with those IGBTs and aggressive/treatment-resistant brain tumors. However, it will be important to consider regulatory, bioethical, and access hurdles regarding these risks to ensure that novel therapies reach as many patients as possible. In conclusion, it can be suggested that cancer vaccines have a high potential to influence the further development of brain cancer treatment strategies due to constant advances in the collaboration of various scientific disciplines.

Biography

Ugwu Okechukwu Paul-Chima is a highly experienced educator with a well-established background in the realm of higher education. His areas of expertise encompass Pharmacological Biochemistry, Food Biochemistry, Clinical and Nutrition Biochemistry, alongside strong leadership skills and a high level of proficiency in research publications. Currently, Dr. Ugwu Okechukwu Paul-Chima holds the positions of Head of Department for Publication and Extension and Deputy Director of Research at Kampala International University, Uganda. He is deeply involved in ongoing research endeavors, concentrating on the domains of Nutritional, Medical, and Pharmacological Biochemistry, with his present project dedicated to the exploration of Pharmacological Research.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

Data used in this study is available within the manuscript.

Consent to publication

All the authors have read and agreed to the final copy as contained in the manuscript.

Statement of ethical approval

This is a review article without primary data collecting or analysis from human subjects or animals. The authors consequently conducted no more patient data or direct treatments, and ethical clearance was not needed. As such, no approval reference number exists.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2526964.