Advancing Brain Tumor Immunotherapy: The Role of Nanomedicine in Primary and Metastatic Brain Tumor

Sandbhor Puja^1*, Mathur Ishita¹, John Geofrey², and Goda Jayant²

¹Translational Nanomedicine and Bioengineering Lab, Department of Radiation Oncology, Advanced Centre for Treatment, Research, and Education in Cancer-Tata Memorial Centre (ACTREC-TMC), Navi-Mumbai 410210, India

²Radiobiology Lab, Department of Radiation Oncology & Homi Bhabha National Institute, Tata Memorial Hospital (TMH), Mumbai, 400012, India

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Abstract

The present mini-review explore the therapeutic potential of nanomedicine in advancing immunotherapy for primary and metastatic brain tumors, addressing existing challenges and paving the way for transformative precision therapy. Primary brain tumors including glioblastoma and metastases from other cancers like breast, lung etc., experiences limitation in treatment outcomes due to the tumor heterogeneity, immunosuppressive tumor microenvironment (TME), the blood-brain-barrier (BBB), and therapy resistance. Although, immunotherapies have shown promising benefits, however are hindered by immune escape, organ toxicities, and variable patient responses. Major unresolved challenges include insufficient therapeutic penetration across the BBB, the inability to reprogram the immunosuppressive TME, limited strategies to counteract dynamic tumor antigen escape, and systemic toxicities associated with conventional therapies. To address these challenges, multifunctional nanomedicines offer promising solutions through precise and controlled delivery, immunosuppressive TME modulation, and/or recalibration of immune system. Advanced nanomaterials including lipid/polymer-based system, dendrimers, and quantum dots, can co-deliver immunomodulators and chemotherapeutic/radiosensitizers, enhances BBB permeability, and activate favorable immune responses. Nanomedicines with multimodality such as localized hyperthermia (e.g. photothermal ablation), and immunogenic cell death stimulate immunological memory and improve therapeutic benefits. Furthermore, innovation in gene therapy (e.g. CRISPR-Cas9) and personalized cancer vaccines enhance targeted anti-tumor immune responses. Despite these groundbreaking advancements challenges persist, including nanoparticles-biological interactions (protein corona effects), stability, scalability, and regulatory hurdles. However, emerging trends such as 3D organoids, organ-on-a-chip system, patient-derived xenografts, and integration of AI/ML platforms, offer physiologically relevant platforms to optimize nanotherapy with better response predictions. Moreover, surface functionalization such as solid-lipid nanoparticles targeting programmed death–ligand 1 (PD-L1)-epidermal growth factor receptor (PD-L1/EGFR), have demonstrated success in augmenting the abscopal effect of radiotherapy. Radiotherapy enhances tumor antigen cross-presentation by inducing immunogenic cell death (ICD), leading to the release of tumor-associated antigens (TAAs). This process is accompanied by the release of damage-associated molecular patterns (DAMPs), such as calreticulin, HMGB1, and ATP. These signals recruit and activate dendritic cells (DCs), which engulf tumor antigens and process them via the major histocompatibility complex (MHC) class I, facilitating the activation of cytotoxic T lymphocytes (CTLs) against the tumor (S. Zhu et al., 2022). Nanoparticles (NPs) can improve antigen delivery by encapsulating tumor antigens and immune-modulatory agents, ensuring prolonged antigen presentation. Furthermore, radio-enhancing NPs, such as gold or hafnium oxide nanoparticles, intensify the effects of radiation by increasing DNA damage and reactive oxygen species (ROS) production, which strengthens the ICD response and improves antigen release (He et al., 2025). In order to further enhance immune activation, some NPs are also designed to modulate the tumor microenvironment by promoting pro-inflammatory signaling.

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Nanomedicine offers a solution by using nanoparticles to enhance drug delivery and retention within tumors, reducing off-target effects. NPs passively accumulate in tumor tissues due to leaky vasculature and impaired lymphatic drainage. Beyond passive accumulation, functionalized NPs with targeting ligands improve tumor specificity, reducing systemic toxicity. Controlled-release mechanisms ensure sustained drug exposure, optimizing the therapeutic index of chemotherapy while promoting tumor antigen release and dendritic cell activation, thereby enhancing immune responses (Fan et al., 2023)

Additionally, theranostic nanoplatforms integrating real-time imaging and therapy show promise for precision neuro-oncology. Though clinical translation is ongoing, interdisciplinary collaboration is essential to integrate nanomedicine with multimodalities, addressing therapy resistance, recurrences, and delivery across the BBB. This mini-review underscores nanomedicine’s transformative potential in brain tumor immunotherapy with other multimodalities, offering hope for safer, and more effective treatments in one of neuro-oncology’s most challenging fields.

This special mini-review, titled Advancing Brain Tumor Immunotherapy: The Role of Nanomedicine in Primary and Metastatic Brain Tumor, aims to provide an in-depth exploration of the current challenges and novel strategies in the therapeutic paradigm of primary and metastatic brain tumors, focusing on the transformative potential of nanomedicine. The review also seeks to foster a broader interdisciplinary dialogue aimed at overcoming the limitations of existing therapies, paving the way for more effective treatments in the future.

Primary brain tumors, like high-grade gliomas (e.g., glioblastoma), as well as brain metastases from cancers like breast cancer, lung cancer, colon cancer, etc.(Lah et al., 2020); are typically treated with a combination of surgery, adjuvant chemotherapy, radiotherapy, and/ or immunotherapy in the contemporary era. However, these conventional treatment modalities face significant limitations in clinical efficacy and excessive toxicities leading to difficulties in optimizing these therapies for therapeutic gain. Primary and metastatic brain tumors differ significantly in their immunological and microenvironmental landscapes. Glioblastomas, for instance, exhibit a uniquely immunosuppressive TME dominated by tumor-associated macrophages (TAMs), regulatory T-cells (Tregs), and limited neoantigen diversity (Zhang et al., 2022). In contrast, brain metastases (e.g., from melanoma or lung cancer) often retain immune profiles reflective of their primary tumors, with higher tumor mutational burden and immune cell infiltration. However, both are constrained by the BBB, which restricts immune cell trafficking and systemic drug delivery. These differences underscore the need for tailored nanomedicine strategies to address context-specific barriers (Exley et al., 2022). These challenges are aggravated by the immunosuppressive tumor microenvironment (TME), the inherent tumor heterogeneity, anatomical barriers that prevent complete surgical resection, and the blood-brain barrier (BBB)/blood-brain-tumor-barrier (BBTB), which restricts the efficient delivery of systemic therapeutics. In contrast to the intact BBB, the blood–brain tumor barrier (BBTB) exhibits heterogeneous permeability due to the abnormal vasculature in tumors. While the BBB maintains strict regulation of molecular transport and immune cell entry via tightly sealed junctions, the BBTB often displays impaired tight junctions and leaky vasculature. This altered barrier facilitates enhanced permeability albeit inconsistently resulting in variable transport of therapeutic molecules. Moreover, the BBTB can allow greater immune infiltration compared to the intact BBB, which has important implications for both nanoparticle delivery and immunotherapy (Belykh et al., 2020) (Choi et al., 2025). Although immunotherapy has emerged as an encouraging strategy that leverages the host immune system to combat tumors, poor patient responses, inflammatory reactions, systemic toxicities, and hematopoietic dysfunction during clinical treatments have hindered its success. To advance the impact of immunotherapies, this special mini-review highlights the mechanistic insights into how primary and metastatic brain tumors evade immune detection and outlines how nanomedicine can be harnessed in combination with multimodal therapies to re-educate the immunosuppressive TME. Despite breakthroughs in systemic cancers, conventional immunotherapies face unique challenges in brain tumors. The BBB limits the penetration of monoclonal antibodies (e.g., anti-PD-1/ PD-L1), while the brain’s immune privilege marked by low MHC-I expression, limited dendritic cell activity, and immunosuppressive cytokines (e.g., TGF-β) hinders antigen presentation. Additionally, glioblastomas exhibit intrinsic resistance via PTEN loss or WNT/β-catenin activation, which suppress T-cell infiltration. Metastatic tumors, though more immunogenic, often develop adaptive resistance through upregulation of alternative checkpoints (e.g., TIM-3, LAG-3). These factors collectively explain the limited clinical success of immunotherapy in neuro-oncology, necessitating nanotechnology-driven solutions (Fares et al., 2023) (Y. Liu et al., 2024)

Graphical abstract: Challenges in Nanomedicine-Based Multimodal Cancer Therapy

A critical challenge in treating malignant brain tumors is the cold tumor microenvironment, one of the important hallmarks of cancer progression (Quail & Joyce, 2017), which allows tumor cells to evade immune surveillance. This  immune  escape  occurs  through  a  variety  of mechanisms, including the presence of immunosuppressive antigen-presenting cells (APCs), impaired trafficking and priming of T-cells, exhaustion of cytotoxic T-cells, low immunogenicity of tumor antigens, and disorganized tumor vasculature. In the brain tumor microenvironment, TAMs adopt an M2-like phenotype that promotes tumor progression by secreting immunosuppressive cytokines (IL-10, TGF-β), expressing immune checkpoint molecules (PD-L1), and facilitating tissue remodeling. Nanomedicine strategies aim to repolarize TAMs to an M1 phenotype, enhancing pro-inflammatory responses and restoring antitumor  immunity.  Similarly,  MDSCs  accumulate in tumors, releasing arginase, inducible nitric oxide synthase, and reactive oxygen species that impair T cell function. Nanomedicine platforms are being explored to inhibit these suppressive mediators or promote MDSC differentiation into less immunosuppressive myeloid cells. Tregs, enriched in brain tumors via TGF-β signaling, suppress cytotoxic T lymphocytes and promote an anti-inflammatory environment. Nanomedicine approaches now focus on selectively depleting or reprogramming Tregs to counteract their immunosuppressive effects (Y. Zhu et al., 2020).. Although immune checkpoint inhibitors (ICIs) like Pembrolizumab have demonstrated efficacy in various systemic cancers, their benefit in brain tumors remains limited. This is largely attributed to two factors. First, the BBB significantly restricts the delivery of both therapeutic antibodies and the infiltration of activated T cells into the brain parenchyma. Second, brain tumors often exhibit a ‘cold’ immune microenvironment characterized by low T cell infiltration and high levels of immunosuppressive mediators, which further dampens the activity of ICIs. Consequently, strategies that combine nanomedicine to modulate the tumor microenvironment with ICIs may be required to enhance their therapeutic impact in brain cancers (Sanders & Debinski, 2020). In this context, nanotechnology offers a promising solution by integrating multiple therapeutic functions within nanoparticles of controlled size and shape, providing a unique platform for developing brain tumor microenvironment-responsive advanced immunotherapies.

Nanoparticle delivery strategies can be broadly classified into active and passive targeting approaches. Active targeting utilizes ligand-mediated recognition to engage specific receptors/proteins overexpressed on tumor cells or tumor-associated endothelium, thereby facilitating receptor-mediated transcytosis/endocytosis. In contrast, passive targeting exploits the enhanced permeability and retention (EPR) effect, where nanoparticles accumulate in tumor tissues due to the leaky vasculature characteristic of the BBB/BBTB (Bertrand et al., 2014). An explicit comparison of these strategies reveals that while active targeting may offer higher specificity, it often depends on receptor expression levels that can vary within the tumor, whereas passive targeting is limited by the heterogeneous nature of the EPR effect. Furthermore, the translational success of these nanoparticles is highly dependent on their stability in the brain’s environment and their clearance mechanisms. For instance, nanoparticles must resist degradation and avoid rapid uptake by resident microglia or clearance via lymphatic routes to ensure sustained therapeutic delivery (Lai et al., 2024).

Figure 1: Schematic representation of the immunosuppressive tumor microenvironment (TME) in brain tumors, highlighting key components that contribute to the establishment of a “cold” TME. This figure also illustrates current multimodal therapeutic approaches aimed at reprogramming the TME to a “hot” state, with the goal of enhancing immune response and improving treatment outcomes.

Nanoparticles, including polymers, lipids, metals, and inorganic/organic nanocomposites, have been explored as vehicles for co-delivering immunomodulators and therapeutic agents. These advanced nanomaterials can selectively target tumor cells through active or passive targeting mechanisms, allowing for precise delivery of drugs and immunomodulators/immunostimulants while overcoming the limitations imposed by the BBB. A recent study by Ni et al summarizes the efforts to convert the cold immunosuppressive brain tumor microenvironment into a hot tumor microenvironment conducive to immunomodulation (Ni et al., 2023). Moreover, neuro-oncology research has made significant strides in spatiotemporal immunomodulation strategies that utilize nanomedicines, employing localized tumor cell killing through combinatorial approaches, including hyperthermia, photothermal tumor ablation (e.g. photothermal therapy, photodynamic therapy), and ultrasound-mediated drug delivery (Y. Zhao et al., n.d.). These localized therapies stimulate the release of tumor-associated antigens (TAAs) and pro-inflammatory cytokines, which, in turn, activate the immune system and promote the generation of innate immune memory to inhibit tumor recurrence and metastasis.

Furthermore, chemotherapy has been shown to induce immunogenic cell death (ICD), illustrated by the discharge of danger-associated molecular patterns (DAMPs), such as calreticulin, HMGB1, and ATP, from the dying tumor cells. These signals act to promote APC activation and stimulate an anti-tumor immune response (Decraene et al., 2022). Similarly, low-dose radiation therapy (<2 Gy per fraction) can synergize with ICD by facilitating the release of TAAs, which are then captured by APCs and used to prime cytotoxic T-cells. In contrast, nanoparticle-mediated ICD and conventional radiotherapy-induced ICD share the common goal of releasing DAMPs and tumor-associated antigens to stimulate an adaptive immune response. However, nanoparticle-driven ICD offers several advantages: it can be precisely localized and tuned to produce a controlled thermal or photodynamic effect, thereby inducing ICD at lower energy levels and reducing collateral tissue damage. In contrast, radiotherapy relies on high doses of ionizing radiation to generate ROS and DNA damage, which, while effective, may also damage be surrounding healthy tissues (A. V. Singh, Chandrasekar, et al., 2024). For instance, neoadjuvant triplet immune checkpoint blockade in a newly diagnosed glioblastoma patient markedly increased tumor-infiltrating, activated T cells and was associated with a 17-month recurrence-free survival (Long et al., 2025). These activated T-cells are directed at both the primary and metastatic tumor sites via lymphatic and circulatory pathways, triggering an “abscopal effect”—an immune-mediated response that controls distant tumor growth. However, tumor cells often evade this immune response by upregulating inhibitory molecules, such as PD-L1, CTLA-4, and others, that prevent effective T-cell signaling and immune-mediated tumor elimination (Daguenet et al., 2020).

Recent work by Liu et al. (2023) and Quader et al. (2022) provides a comprehensive overview of the development of nanomaterials, including liposomes, micelles, lipid nanoparticles, dendrimers, quantum dots, carbon/DNA nanotubes, and organic/inorganic nanoparticles (e.g. MOFs), for the treatment of both primary and metastatic brain tumors (D. Liu et al., 2023), and (Quader et al., 2022). These nanoparticles can be functionalized to target tumor cells more effectively and facilitate the co-delivery of chemotherapy with immunotherapeutic agents, further enhancing the immune response. Notably, Erel-Akbaba et al demonstrated that solid-lipid nanoparticles, functionalized with cRGD and co-loaded with small interfering RNA (siRNA) targeting EGFR and PD-L1, could enhance the abscopal anti-tumor response of radiation therapy in glioblastoma (Erel-Akbaba et al., 2019). Li et al utilized theranostic nanoprobes, such as PEG-catalase and cRGD-modified quantum dots, to promote ICD and improve the anti-tumor immune response in lung metastasis. These studies underscore the potential of combining nanomedicines with immunotherapy and radiation to overcome immune suppression within the TME (Li et al., 2023). A systematic review conducted by Kamaly et al., highlighted maximizing the therapeutic efficacy of toxic chemotherapies and other active pharmaceutical ingredients (APIs) requires precise drug delivery and controlled release at the disease site. For stimuli-responsive polymeric nanoparticles to gain widespread clinical adoption, thorough testing and validation of these responsive materials are essential, especially given the numerous emerging polymers that have yet to undergo clinical evaluation (Kamaly et al., 2016).

Gene therapy, such as CRISPR-Cas9 based gene editing, has shown promise in targeting specific genes involved in the proliferation, migration, invasion, angiogenesis, and apoptosis of malignant brain tumor cells. CRISPR-Cas9, while offering precise gene editing, carries the risk of off-target effects, which can lead to unintended genetic modifications and potential oncogenic transformations (Merlin & Abrahamse, 2024). Cancer vaccines aim to train the adaptive immune system to recognize tumor-specific antigens or mutations. Neoantigen-based vaccines are highly personalized and immunogenic but require complex sequencing, whereas peptide-based vaccines target shared tumor antigens, making them more broadly applicable but less immunogenic (Xie et al., 2023). A Phase-1b study in 2019 demonstrated that neoantigen vaccines could increase T-cell infiltration in glioblastoma patients following surgery and adjuvant radiotherapy, providing evidence for the potential of personalized immunotherapy in brain cancer treatment (Keskin et al., 2019). However, tumor immune escape mechanisms, such as antigen loss (e.g., EGFRvIII loss) and MHC downregulation, can limit cancer vaccine effectiveness by allowing tumors to evade immune detection. This highlights the need for multi-targeted approaches in vaccine design to improve immunotherapy success.

Among the various strategies for gene therapy, the electrostatic interaction between cationic biomaterials and anionic nucleic acids has emerged as a critical mechanism for self-assembling nanoscale electrostatic complexes (Krieger et al., 2022). These complexes, commonly referred to as non-dendrimer nanoparticles, encompass a range of non-viral systems, such as lipoplexes (lipid-based) and polyplexes (polymer-based), that are widely studied for gene delivery applications in brain tumor therapy. In the context of brain tumor nano-immunotherapy, electrostatic interactions facilitate the formation of coordination complexes between positively charged (cationic) nanoparticles and negatively charged nucleic acids (e.g., siRNA, plasmid DNA). This interaction enables the efficient delivery of genetic material to the tumor site by overcoming cellular barriers and promoting internalization through endocytosis. The electrostatic binding between the cationic nanoparticles and anionic nucleic acids leads to the formation of lipoplexes/ polyplexes (lipid-based/ polymer-complexes), which can be tailored to improve their biocompatibility, stability, and controlled release properties for targeted therapy. Both of these nanocarriers have been extensively explored in preclinical models for their potential to deliver immunomodulatory agents, such as immune checkpoint inhibitors, cytokines, or gene-editing tools like CRISPR-Cas9, to reprogram the immune TME of glioblastoma and other brain cancers (Tros de Ilarduya et al., 2010). In addition to lipoplexes and polyplexes, several other synthetic nanomaterials have shown promise in brain tumor immunotherapy. These include spherical nucleic acids, solid-lipid nanoparticles, polymersomes, polymeric micelles, and dendrimers, each offering unique advantages in terms of drug encapsulation, cellular uptake, and BBB penetration (Mitchell et al., 2021). For example, spherical nucleic acids (SNAs) represent a novel class of nanomaterials with a unique architecture that enhances their interaction with cellular membranes, facilitating efficient uptake by brain tumor cells reported in first-in-human phase-0 clinical study (Kumthekar et al., 2021a). These SNAs, along with solid-lipid nanoparticles (SLNs), have been explored for their ability to deliver gene therapies and immune-modulating agents (e.g; dostarlimab, Nivolumab, Pembrolizumab) to brain tumors (Satapathy et al., 2021). As summarized by Zhao et al., high lipophilic nanoparticles with molecular weights below 500 Da have been known to penetrate through rigid BBB. Polymer nanoparticles with charged drug-loaded surfaces have caused instant transcytosis through brain capillary walls. Tissue inhibitor of matrix metalloproteinases 1 (TIMP1) was loaded in biodegradable synthetic polymers, Poly (lactide-glycolide) (PLGA) copolymers nanoparticles with polysorbate 80-coating through electrostatic attachment and highest encapsulation efficiency was to the extent of 83.42%. PLGA nanoparticles with diameters between 80 to 432 nm contained hydrophilic and negative charged surface due to presence of ample number of carboxy groups. Though these nanoparticles failed to open BBB substantially, however, these nanoparticles have enhanced delivery of protein through endothelial cell boundaries. NPs should thus be surface charged and/ or targeted to achieve adsorptive transcytosis or receptor mediated transcytosis to attain better protein delivery through BBB (H. Zhao et al., 2016). Recent reviews, such as the one by Kogel et al., provide valuable insights into the current landscape of non-viral vector-based systems for brain tumor therapy, focusing on the integration of gene therapy and immunotherapy with nanomedicine (Kögel et al., 2025). These nanoplatforms are not only designed to enhance therapeutic payload delivery but also to trigger immune activation in the TME, improving overall treatment outcomes.

Recent clinical studies have explored the use of nanoparticles in combination with other therapies, such as chemotherapy and immunotherapy, to overcome the multifaceted challenges of glioblastoma and other high-grade brain tumors. For instance, a study utilizing liposomes modified with transferrin receptor-targeting ligands demonstrated the potential for targeted delivery of a wild-type TP53 encoding plasmid in combination with the chemotherapeutic agent temozolomide. The delivery system effectively crossed the BBB in preclinical glioblastoma mouse models, triggering significant antitumor immune responses. However, the Phase-II clinical trial (NCT02340156) of this approach was terminated due  to  insufficient  patient  enrollment,  highlighting the challenges in translating these therapies to clinical practice. Despite this setback, TP53-targeted therapies are being further pursued in other cancer types, such as pancreatic cancer, underscoring the broader potential of nanomedicine for targeting tumor cell death pathways. Similarly, the use of siRNA-based brain-penetrant gold nanoparticles targeting the Bcl2L12 gene in recurrent glioblastoma has shown promising results in preclinical models. The Phase-0 study (NCT03020017) demonstrated significant enrichment of gold nanoparticles within the tumor microenvironment, leading to the downregulation of Bcl2L12 proteins, which are implicated in tumor cell survival and resistance to therapy. These studies suggest that nanoparticle-based gene silencing strategies can effectively modulate key pathways involved in brain tumor progression and resistance.

Recent advancements in nanomedicine-based immunotherapies targeting glioblastoma and metastatic brain tumors focus on strategies that improve immune response and therapeutic efficacy. Several new approaches are currently in preclinical and clinical evaluation, utilizing nanotechnology to enhance drug delivery, immune activation, and tumor targeting. In Phase II studies for GBM, Gliovac, a vaccine made of autologous and allogeneic tumor lysates, aims to reduce immune escape (Bota et al., 2018a). Similarly, PVSRIPO is in Phase I/II studies in combination with anti-PD-1 (Pembrolizumab), a recombinant poliovirus-rhinovirus chimera, which targets CD155+ GBM cells and has long-term survival benefits (Sloan et al., 2021). Iron oxide nanoparticles (Ferumoxytol) in conjunction with PD-1 blockade are another promising strategy that is being evaluated in Phase I/II for GBM and lung cancer brain metastases (Huang et al., 2022a). This approach offers a theranostic advantage with MRI-guided immune checkpoint inhibition and has been tested in syngeneic brain metastases models. Other novel approaches include Spherical Nucleic Acid (SNA) Nanoparticles (siBcl2L12-SNAs), which are presently in a Phase 0 clinical trial and have shown the potential and safety of gene silencing in GBM patients (Kumthekar et al., 2021b). These nanoparticles use RNA interference (RNAi) to silence the Bcl2Like12 gene in orthotopic GBM mouse models. The liposomal doxorubicin (Doxil) with anti-PD-1 antibody has demonstrated chemo-immunotherapy combination in preclinical models, enhancing T-cell infiltration and tumor death . Hydrogel-based CAR-T cell administration is another innovative approach. It has been evaluated in preclinical models, showing improved tumor suppression and CAR-T survival (Grosskopf et al., 2022). . Additionally, in syngeneic glioma models RNA-loaded lipid nanoparticles (LNP-TGFβ Inhibitor), which are intended to alter the immune environment by inhibiting TGFβ, showed a 37% improvement in anti-tumor activity (Grippin et al., 2019a). When taken as a whole, these nanomedicine strategies provide revolutionary breakthroughs in brain tumor immunotherapy, utilizing gene silencing, immunological modulation, and targeted drug delivery to overcome treatment resistance and enhance patient outcomes.

Table 1: Nanomedicine-Based Immunotherapies in Clinical Trials for Primary and Metastatic Brain Tumors

S.No.	Nanomedicine	Composition	Tumor Type	Therapeutic Target/ Mechanism	Clinical Trial Phase	Outcome/ Status	Ref.
1.	ERC1671 (Gliovac)	Autologous and allogeneic tumor cell lysates	GBM	Stimulates immune response against tumor antigens	Phase II	Ongoing, aims to reduce immune escape	(Bota et al., 2018b)
2.	PVSRIPO with anti-PD-1 mAb (pembrolizumab)	Recombinant non-pathogenic polio-rhinovirus chimera	GBM	Targets tumor cells expressing CD155; induces anti-tumor immune response	Phase I/ II	Early trials show promising survival benefits	(Sloan et al., 2021)
3.	Iron Oxide Nanoparticles (Ferumoxytol) + Anti-PD-1	Superparamagnetic iron oxide nanoparticles	GBM, Brain mets from lung cancer	MRI-guided immune checkpoint blockade	Phase I/II	Under clinical evaluation	(Huang et al., 2022b)
4.	Spherical Nucleic Acid (SNA) Nanoparticles (siBcl2L12-SNAs)	Nanoparticles with radially oriented oligonucleotides delivering siRNA targeting Bcl2Like12	GBM	Gene silencing via RNA interference (RNAi)	Phase 0	Demonstrated safety and potential for therapeutic efficacy in patients with recurrent GBM	(Kumthekar et al., 2021c)
5.	Liposomal Doxorubicin (Doxil) + Anti-PD-1	Liposome-encapsulated doxorubicin + ICI	GBM, Brain mets from breast cancer	Synergistic chemo-immunotherapy	Preclinical (CT26 or MCA205 tumor model)	Potential for improved outcomes	(Rios-Doria et al., 2015)
6.	Gel-Based Delivery of CAR-T Cells	Hydrogel-encapsulated CAR-T cells targeting tumor-specific antigens	GBM	Localized CAR-T cell therapy	Preclinical (MED8A tumor model)	Enhanced CAR-T cell survival and tumor suppression in pre-clinical models	(Grosskopf et al., 2022)
7.	RNA- Loaded Lipid Nanoparticles (LNP-TGFβ Inhibitor)	Lipid nanoparticles delivering siRNA against TGFβ	GBM, Brain mets from lung cancer	Immune microenvironment modulation	Preclinical (Brain tumor model)	Enhanced anti-tumor efficacy	(Grippin et al., 2019b)

Substantial work has also been conducted to improve the retention of therapeutic payload for primary and metastasis brain tumors. While these approaches hold significant promise, several key challenges remain in the field of nanomedicine-based brain tumor immunotherapy. The BBB continues to be a major barrier, limiting the efficient delivery of therapeutic agents to the brain. In this context, Wyatt et al reviewed various strategies such as functionalization with targeting ligands (e.g., PDGFR, transferrin, folate, RGD peptides) and the development of nanoparticles with intrinsic BBB-circumventing capabilities like through intranasal administration, loco- regional drug delivery (e.g. wafers, injectable implants, convection enhanced delivery), and ultrasound assisted trigger responsive systems etc. are being explored to improve brain availability and precision with an aim to increase therapeutic outcomes (Ea & Me, 2020)

A recently published Phase-I clinical study has demonstrated the potential of combining a radiosensitizer with a single-dose treatment of gadolinium (Gd)-based ultra-small nanoparticles (AGuIX) in patients with brain metastases originating from primary cancers, including breast, lung, colon, and melanoma. This study underscores the broad translational potential of theranostic multifunctional nanoplatforms, which integrate both therapeutic and diagnostic capabilities(Verry et al., 2020). These nanoplatforms have shown the ability to provide real-time tumor responses to therapy, facilitating enhanced monitoring of metastasis during treatment. The incorporation of Gd-based nanoparticles not only improves the precision of radiotherapy by sensitizing tumors to radiation but also enables advanced imaging techniques to assess the therapeutic efficacy in real-time, offering significant promise for personalized and targeted cancer treatment strategies in metastatic brain tumors.

Figure 2: Schematic representation of the key challenges in the treatment of primary and metastatic brain tumors, including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), cancer stem cell (CSC) niches, multidrug resistance (MDR), epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), epigenetic alterations such as DNA methylation, resistance to DNA damage induced cell death, hypoxic microenvironments, and the protein corona effect. A supplementary panel highlights emerging technologies, including organoids, organ-on-a-chip models, and cutting-edge artificial intelligence (AI) tools, which are essential for developing physiologically relevant in vitro systems to better understand and address these complex challenges

Despite significant technological advancements in conventional anticancer treatments, tumor recurrence and treatment resistance remain major challenges, particularly in the context of advanced primary and metastatic brain tumors. As highlighted in a review by Singh and Settleman, various mechanisms contribute to this persistent problem, including epithelial-mesenchymal transition (EMT), upregulation of multidrug resistance (MDR) or detoxification proteins (e.g., aldehyde dehydrogenase), the role of the cancer stem cell (CSC) niche and their dormancy, tumor microenvironment (TME factors), resistance to DNA damage-induced cell death, epigenetic alterations, hypoxia, and DNA methylation (A. V. Singh, Bhardwaj, et al., 2024) (A. Singh & Settleman, 2010) Conventional chemotherapy fails to completely eradicate CSCs, which possess the ability to differentiate into new tumor cells, thereby promoting tumor metastasis and recurrence. These CSCs contribute to cancer cell dissemination and invasion, exploiting the dynamic and supportive environment of the brain microenvironment.  They evade immune recognition through mechanisms such as modulating the tumor immune microenvironment (TIME) and altering surface antigen expression (e.g., CD133, CD44), allowing them to resist innate and adaptive immune responses. Nanomedicine offers promising solutions by utilizing nanoparticles engineered to selectively target CSC markers, thereby enhancing immune-mediated elimination (Zeng, 2024, and Moussa, 2025.). Ultrasmall gold nanoparticles, for instance, have demonstrated efficacy in reducing CD133-associated stemness (Verma, 2024). Additionally, epigenomic reprogramming via nanomedicine holds the potential for reversing CSC plasticity, making them more vulnerable to immune attack. While this approach shows promise, challenges such as ensuring specificity and minimizing off-target effects (Ali et al., 2024).

Figure 3: Overview of various nanoplatforms and their targeting mechanisms for primary and metastatic brain tumors. This includes receptor-mediated endocytosis (RME) via ligand functionalization, passive targeting through the enhanced permeability and retention (EPR) effect, biomimetic camouflaging for immune system evasion, augmenting immunogenic cell death via radiotherapy, thermal ablation of tumor for localized killing of tumor cells, targeting cancer stem cells, and the delivery of immune-modulating agents using siRNA/mRNA based nanoparticles. The figure highlights the potential of these combinatorial strategies in improving the precision and efficacy of targeted therapies for brain tumors.

To overcome these challenges, a promising approach involves integrating nanomaterials with immunotherapy and other multimodal treatment strategies to specifically target CSCs and the tumor microenvironment. Such strategies hold significant promise for improving the efficacy of cancer treatments, particularly for advanced brain tumors. In a recent article by our research team, we extensively reviewed the role of CSCs in tumor progression and recurrence, with a focus on innovative nanomedicines designed to target CSCs and the TME (Sandbhor et al., 2024). Despite the development of various nanoplatforms combined with other therapies aimed at enhancing target specificity and tumor penetration, their clinical success has been less than anticipated. A significant limitation arises from the interaction of nanoparticles with the biological environment, which often results in the formation of a “protein corona”. This corona can alter the normal function and fate of the nanoparticle formulations, reducing their effectiveness in preventing tumor progression. To enhance nanoparticle stability and functionality, various surface modifications have been explored, thereby addressing the protein corona challenge. For instance, strategies like PEGylation, biomimetic camouflaging, and zwitterionic coatings have demonstrated potential in reducing protein adsorption and aim to preserve nanoparticle integrity. Zwitterionic coatings offer electrostatic neutrality that prevents nonspecific protein interactions, whereas PEGylation provides a steric barrier that minimizes opsonization while prolonging the circulation time. (Tian et al., 2025) (Suk et al., 2016). Biomimetic modifications, like the use of cell membrane-coated nanoparticles, have been investigated to evade immune recognition and enhance tumor-specific delivery, aiming to mitigate the effects of the protein corona. (Oh et al., 2018)

In addition to these challenges, safety concerns, the need for regulatory approvals, and the difficulties associated with mass production and lack of established FDA guidelines for nanomedicines present significant barriers to the clinical translation of nano-assisted drug delivery. To better predict and optimize the responses to nanotherapy, the development and use of well-characterized, physiologically relevant models, such as organ-on-a-chip, 3D organoids, and patient-derived xenograft (PDX) models, are critical. These models play a pivotal role in bridging the gap between bench and bedside by facilitating the optimization of nanomedicines. These advanced ex-vivo/in-vivo models enable the study of nanoparticle interactions with the tumor microenvironment in physiologically relevant settings.

Beyond their role in therapeutic assessment, these models are crucial in refining nanoparticle formulations to enhance drug loading, release kinetics, and immune interactions, ultimately optimizing the treatment efficacy before any clinical trials. Integrating high-throughput screening with these models can streamline the identification of promising nanomedicine platforms along with their safety and translational potential. These models, when coupled with appropriate safety and tolerability endpoints, could significantly advance the field of precision therapy for both primary and metastatic brain tumors, ensuring that nanomedicines are more effective in clinical settings.

Collectively, the era of multimodal nano-immunotherapy has accompanied in a paradigm shift in the treatment of advanced primary and metastatic brain tumors. Technological advancements in the development of multifunctional nanoplatforms, including combinatorial designs for precision drug delivery, and immune modulation, have shown immense promise in overcoming critical challenges such as the blood-brain barrier, treatment resistance, and tumor recurrence. Han et al. conducted a comprehensive review highlighting how biomaterials and biotechnology, spanning from the nanoscale to the macroscale, are revolutionizing immunotherapy. Acting as drug delivery systems, both natural and synthetic biomaterials function like robotic carriers, facilitating the transport, protection, delivery, and controlled release of immunomodulatory agents. By tailoring key properties such as composition, size, shape, charge, and surface modifications, these biomaterial-based devices can enhance stability, optimize drug delivery efficiency, achieve favorable pharmacokinetics and targeted biodistribution, ensure responsive activation, and minimize systemic adverse effects. (S et al., 2020) According to another review by Han et al., biomaterial-based strategies have evolved into highly customizable platforms among which, 3D macroscale biomaterials have emerged as a crucial class, offering advantages over other biomaterials. The integration of biocompatible macromaterials with cancer immunotherapy is both unique and essential, potentially leading to more reliable preclinical outcomes and effective treatments. A key advantage of 3D macroscale biomaterials lies in their ability to deliver adjuvants in a localized and anchored manner. Their structured design helps address concerns associated with systemic administration. Once the target site is identified and accessible, these bulk biomaterials can be locally applied via injection or implantation, facilitating precise tumor immunomodulation. Notably, they also complement both localized and systemic cancer immunotherapy. Given that over 90% of cancer-related deaths result from metastasis and relapse, an ideal therapeutic approach should not only target the tumor microenvironment (TME) in situ but also effectively activate systemic immunity. (Han & Wu, 2022) Despite these advancements, clinical translation remains delayed by limitations such as nanoparticle-biological interactions (e.g., protein corona effects, unexpected pharmacokinetics), scalability, regulatory challenges, and safety concerns. The integration of nanomedicines with immunotherapy provides a transformative opportunity to improve treatment specificity, reprogram the immunosuppressive TME, and precisely target CSCs and their niche, which are pivotal in brain tumor progression and resistance. Recent advances in preclinical models, such as 3D organoids, organ-on-a-chip systems, patient-derived xenografts, and AI/ML interfaces have the potential to accelerate the understanding of nanomedicines in physiologically accurate settings, ultimately paving the way for personalized and precision therapies (Chandrasekar et al., 2025). AI-driven modeling, which includes deep learning-based nanoparticle design optimization and predictive pharmacokinetic/pharmacodynamic simulations, has been revolutionizing nanomedicine by enabling rapid screening of physicochemical properties, biodistribution, and therapeutic efficacy (Chandrasekar et al., n.d.). While significant strides have been made, the collaborative efforts of multidisciplinary research, translational studies, and regulatory frameworks are critical to bridging the gap between lab scale discoveries and clinical implementation. The future of brain tumor treatment lies in advancing these innovative technologies toward safe, effective, and accessible therapies, offering hope for improved outcomes in one of the most challenging domains of oncology.

In conclusion, we would like to extend our sincere gratitude to the esteemed researchers whose significant contributions have greatly advanced the field of nano-assisted brain tumor therapy. We also acknowledge the peer reviewers for their insightful and thoughtful comments, which have greatly enhanced the quality of this special mini-review in the Journal of Immunological Sciences. Furthermore, we express our deep appreciation to Dr. Emily Bennison, Editorial Manager of the Journal of Immunological Sciences, for her kind invitation and continued support throughout the entire process. We hope that the articles in this special collection will provide valuable insights for both established researchers and emerging investigators in the field of nanomedicines for advanced brain cancer immunotherapy.

Acknowledgement

The authors would like to acknowledge that this mini-review does not involve original research; therefore, no external funding was required for its completion. We thank the relevant institutions and researchers whose valuable insights contributed to the development of this field. The figures in this manuscript were created by the authors using a paid version of Biorender, a graphic design tool for scientific illustrations. The authors confirm that no AI-generated elements were used in the creation of these figures.

Conflicts of interest

The authors declare no competing interests.

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