Engineering hope: biomaterial strategies against glioblastoma

1 Introduction

Glioblastoma multiforme (GBM), classified as a World Health Organization (WHO) grade 4 astrocytoma IDH-wildtype, is the most aggressive brain tumor and remains one of the most difficult-to-treat malignancies (Nozhat et al., 2023). The incidence rate is about 3.19 per 100,000 cases annually and patients typically live 12–18 months after diagnosis. Despite significant advances in the research field, the most effective treatment strategy for GBM still relies on surgical resection followed by chemotherapy, which requires the administration of cytotoxic agents. Currently, four FDA-approved drugs, temozolomide, lomustine, carmustine, and bevacizumab, have been approved to treat the high-grade gliomas and relieve symptoms (Fisher and Adamson, 2021). These drugs are able to cross the blood-brain barrier (BBB) by exploiting different mechanisms. Specifically, lomustine, carmustine, and temozolomide are small and lipophilic molecules that exploit a passive diffusion to penetrate the BBB; whereas bevacizumab is a large monoclonal antibody that can cross the BBB when it is disrupted or compromised. Specifically, the standard care involves mainly the treatment with temozolomide (TMZ) combined with radiotherapy, (Singh et al., 2025), providing a modest survival compared to radiotherapy alone (Jezierzanski et al., 2024). Unfortunately, in some patients, TMZ treatment fails due to the development of resistance mechanism associated with an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, which enables efficient DNA repair. However, prolonged TMZ treatments develop many resistance mechanisms including DNA repair mechanisms, activation of autophagy, and epigenetic alterations (Singh et al., 2021), which promote to increased tumor proliferation, migration, and genomic aberrations (Tiek et al., 2018).

Nevertheless, the identification of promising alternatives to TMZ is limited by the need for drugs capable of crossing the BBB, which restricts the passage of molecules larger than ∼400 Da. In fact, the BBB, formed by tightly connected endothelial cells supported by pericytes and astrocytic end-feet, represents one of the most stringent physiological barriers to drug delivery. Although GBM is associated with partial BBB disruption, the resulting blood tumor barrier (BTB) is characterized by highly heterogeneous permeability, abnormal and disorganized vasculature, alterations in cell-cell adhesion with disrupted tight junctions, leading to uneven drug penetration and sub-therapeutic concentrations, particularly in infiltrative tumor regions. Moreover, alterations in BTB include the downregulation of efflux transporters resulting in an increased formation of caveolae and altered transcellular transport.

To address this issue, engineering and customizing biomaterial-based delivery systems allows to achieve a controlled and prolonged drug diffusion, increase drug solubility, and ability to penetrate across the BBB (Barra et al., 2022a; Barra et al., 2022b). The design of innovative biomaterials takes into consideration different parameters such as particle size, surface properties, and morphology, which influence the BBB crossing, biodistribution, and accumulation within the tumor site (Bellavita et al., 2023; Falanga et al., 2024). Biomaterial-based delivery systems offer several advantages, including biodegradability and biocompatibility, specificity and surface tunability, high capacity to drug loading, and ligand functionalization. Through active targeting strategies, these platforms can improve selective uptake by GBM cells and glioma stem-like cells, thereby reducing off-target toxicity and enhancing local drug accumulation. Moreover, biomaterial-based carriers can protect therapeutic agents from premature degradation, prolong systemic circulation, and facilitate transport across biological barriers via passive diffusion or receptor-mediated mechanisms. However, despite these promising features, the clinical translation of biomaterial-based drug delivery systems remains limited for different reasons. For example, in vivo studies do not always mimic the complexity and heterogenicity of glioblastoma, leading to an overestimation of therapeutic efficacy that does not reflect the tumor size, microenvironment, and patients’ response. In addition, the tumor environment is highly enriched in macrophages, which can interact with biomaterials and promote phagocytosis reducing their therapeutic effectiveness. Moreover, another critical factor is the heterogeneity and structural variability of BBB that does not allow drug diffusion reducing the effectiveness observed in preclinical studies.

Based on the biomaterial nature, delivery systems can be divided into organic (liposomes, dendrimer, hydrogels) and inorganic (carbon nanotubes, quantum dots) systems and can be engineered according to the administration route (Figure 1). Given that the majority of GBM recurrences occur near the surgical resection margins, localized delivery approaches can achieve high intracranial drug concentrations while minimizing systemic toxicity. For example, local drug delivery represents a valuable strategy in GBM treatment, as it allows bypassing BBB and directly accessing the tumor site (Cha et al., 2022). In this context, biomaterial-based systems can be produced using different approaches, including electrospinning, and can be designed as implantable or injectable platforms, such as hydrogels, to achieve localized and sustained drug release (Maity et al., 2025). Furthermore, the clinical translational of biomaterials are limited for their local toxicity during implantation, biodegradation profiles, manufacturing scalability and reproducibility, as well as regulatory hurdles. Moreover, although the systemic administration remains the preferred route for its accessibility and ease of use for patients, its effectiveness is often limited by biological barriers including BBB and systemic clearance, reducing the drug accumulation at the tumor site. Consequently, the current research efforts are more focused on optimizing biomaterial-based delivery systems decorated with drugs for systemic administration. In this context, a particular attention is also given to tumor stress response pathways, such as hypoxia, oxidative stress, and autophagy, which can compromise the performance of biomaterials. Hence, their modulation to co-deliver stress-modulating agents or to be stimuli-responsive may help to bypass these limitations.

Herein, we review the natural and synthetic biomaterials used in the design and development of delivery systems in GBM treatment. Firstly, we describe the different types of biomaterials and their relevant physicochemical properties. We then focus on strategies for biomaterial functionalization with therapeutic agents, highlighting how these platforms have been applied to improve drug delivery, targeting, and therapeutic efficacy in GBM models.

2 Types of biomaterials

Biomaterials can be classified according to their origin into natural and synthetic categories (Figure 2). In this section, we describe the most used biomaterials and their applications in the development of delivery systems.

2.1 Natural biomaterials

Natural biomaterials play an important role due to their biocompatibility, structural similarity to the native extracellular matrix, and intrinsic biological activity (Roy et al., 2025). Polysaccharide and protein-based materials such as chitosan, hyaluronic acid, alginate, gelatin, and collagen can actively interact with glioma cells, influencing adhesion, migration, metabolic adaptation, and therapeutic response. Beyond their use as delivery platforms, natural biomaterials enable the development of physiologically relevant three-dimensional models that better reproduce tumor invasiveness and microenvironmental cues compared to conventional two-dimensional cultures (Xie et al., 2024). However, despite these advantages, natural biomaterials present several limitations, such as batch-to-batch variability, weak mechanical strength, fast and uncontrolled degradation, and immunogenicity. Therefore, due to their tunable chemical and mechanical properties, these materials can be engineered to better align with GBM biology and design advanced therapeutic strategies.

2.1.1 Chitosan

Chitosan, a natural polysaccharide consisting of repeated units of D-glucosamine and N-acetyl-D-glucosamine linked by β (1–4) bonds. Chitosan has a good biocompatibility and biodegradability, as well as intrinsic biological properties such as antimicrobial, immunomodulatory and antitumour activity (Younes and Rinaudo, 2015). Chitosan is poorly soluble in neutral conditions, but it dissolves in acidic environments thanks to the protonation of its amino groups. This property can be exploited for the development of pH-responsiveness delivery systems for achieving a controlled manner drug release.

In the GBM context, the protonated amino groups of chitosan within the acidic tumour microenvironment favour strong electrostatic interactions with the cancer cells surface charged negatively. These interactions can alter glioma cells permeability and lead to the loss of intracellular components. Furthermore, chitosan is also able to establish interactions with mitochondrial membranes rich in anionic elements, disrupting the electron transport chain and leading to the excessive production of reactive oxygen species (ROS), which damage the inner mitochondrial membrane. Due to its stereochemical similarity to the hyaluronic acid (HA) which is the main ligand of CD44 receptors involved in critical tumor processes such as cell adhesion, and migration, chitosan-based formulations can compete with HA for CD44 binding, hindering tumor cell adhesion to the extracellular matrix, and reducing their migratory and invasive capacity into surrounding tissues (Chiesa et al., 2018).

Additionally, thanks to its biocompatibility and biodegradability, chitosan is considered an ideal scaffold material development of three-dimensional (3D) porous scaffolds that recapitulate the physical and molecular architecture of the tumor extracellular matrix. These scaffolds can be fabricated using techniques such as gelation, freeze-drying, allowing precise controls over porosity and mechanical stiffness (Florczyk et al., 2013). Overall, chitosan represents a multifunctional biomaterial and scaffold used both for the design of advanced drug delivery systems, but its clinical translation is hampered by its poor solubility at physiological pH, potential variability in degree of deacetylation, and challenges in achieving reproducible large-scale production. (Kievit et al., 2010).

2.1.2 Hyaluronic acid

Hyaluronic acid (HA) is a polysaccharide composed of repeated units of D-glucuronic acid and N-acetyl-D-glucosamine, linked by β (1–4) and β (1–3) glycosidic bonds (Ananthanarayanan et al., 2011). HA is synthesized by hyaluronan synthases (HAS1, HAS2 and HAS3), producing polysaccharides with different molecular weights, while it is degraded by hyaluronidases enzyme (HYAL) (Pashkina et al., 2025). Unlike chitosan, hyaluronic acid is an anionic polymer featured by the carboxyl acid groups usually dissociated at physiological pH (Wang et al., 2025).

As the main component of the cerebral extracellular matrix, HA plays essential structural roles, regulating synaptic plasticity and tissue homeostasis. Specifically, the cell function is influenced by HA molecular weight (Mw) since the low Mw (80–800 kDa) and high Mw (>1,600 kDa) forms induce different cell behaviors (Jensen et al., 2020; Chen et al., 2018). For example, the low Mw HA triggers the production of pro-inflammatory mediators, while the high Mw HA promotes the inhibition of some mediators (Moshayedi and Carmichael, 2013; Rayahin et al., 2015).

In the GBM context, the interaction between HA and the CD44 and RHAMM receptors is a key factor in regulating tumor aggressiveness, stemness, and cell invasiveness. Notably, the outcome of these interactions is highly dependent on HA molecular weight, which modulates receptor activation and downstream signaling pathways. (Figure 3) (Xu et al., 2025; Price et al., 2018).

Exploiting the natural affinity of this receptor-mediated interaction, HA has been widely adopted as a surface coating for nanoparticles to achieve selective targeting of the CD44 receptor in GBM. For example, Hayward et al., developed HA-coated nanoparticles that preferentially accumulated in CD44-overexpressing glioma cells. This approach not only enhances cellular uptake via receptor-mediated endocytosis but also drastically reduces off-target interactions with healthy surrounding tissues (Hayward et al., 2016). However, although CD44-interaction improves the cellular uptake of delivery systems, this does not necessarily translate into increased in vivo efficacy due to tumor heterogenicity and variability across GBM subtypes.

Additionally, the efficacy of HA-decorated delivery systems depends mainly on HA specific spatial configuration. Indeed, it has been demonstrated that the molecular weight and surface density of the HA chains on the nanoparticle shell critically influence binding affinity, internalization pathways, and subsequent intracellular trafficking (Mizrahy et al., 2011).

In addition to receptor-mediated functions, hyaluronic acid actively contributes to the metabolic reprogramming of GBM cells. For example, HA fragments of medium Mw have been observed to increase mitochondrial respiration, supporting tumor adaptation to nutrient-limited environments (Neves et al., 2024). Another example was reported by Bale et al., where they demonstrated that HA influences the tumor metabolism in GBM, acting on the amino acid metabolism via reduction in LAT1 transporter protein expression (Bale et al., 2024).

In view of its structural and signaling functions, HA could be considered a direct therapeutic target in GBM (Seki et al., 2022; Infante et al., 2018), but however, uncontrolled HA degradation can generate pro-invasive fragments, necessitating combinatorial strategies and patient stratification based on HA content and functional imaging biomarkers.

2.1.3 Alginate, gelatine and collagen

Alginate, gelatin and collagen are among the most widely investigated natural biomaterials due to their superior biocompatibility and versatility in the engineering of 3D-platforms capable of recapturing key features of the tumor microenvironment (Xu et al., 2019).

Alginate is an anionic polysaccharide composed of β-D-mannuronic and a-L-guluronic acid residues, which undergoes mild ionic gelation in the presence of divalent cations according to the “egg-box” model. This process allows cells, drugs and nanoparticle to be encapsulated without compromising biological activity. In GBM, alginate-based hydrogels are mainly employed as biologically inert matrices to be functionalized with peptides or combined with more bioactive components (Jeon and Alsberg, 2013).

An interesting application is Glio-Trap system, an implantable hydrogel functionalized with RGD sequence and loaded with chemoattractants such as CXCL12 (Khan et al., 2023), designed to capture residual tumor cells and expose them to localized anticancer agents. In contrast, gelatin, derived from the partial hydrolysis of collagen, retains multiple bioactive sequences that promote cell adhesion can be exploited for drug and gene delivery applications, enabling controlled release of therapeutic payloads. (Tsou et al., 2016; Andreazza et al., 2023).

Collagen is the main protein component of the extracellular matrix and consists of triple helical polypeptide chains rich in glycine, proline and hydroxyproline, which assemble into fibrils providing structural support to tissue (Guzdek et al., 2025).

Although approximately 28 types of collagens have been identified, only one subset plays a particular role in GBM. Type I collagen is the most studied thanks to its capability to arrange in fibrillar networks, while type IV collagen is the main component of the vascular basement membrane promoting tumor cell adhesion and invasion (Egeblad et al., 2010).

Overall, collagen gels are widely employed to investigate GBM invasiveness and glioma stem cell behavior, providing a highly permissive three-dimensional microenvironment. (Kaphle et al., 2019).

Beyond its role as a structural and modeling material, collagen has increasingly been explored as an active therapeutic platform, with particular emphasis on the following strategies:

• As a vector for in situ chemotherapy, leveraging its high biocompatibility and biodegradability to achieve controlled local release of cytotoxic agents, reducing systemic side effects and bypassing the limitations of the BBB (Guzdek et al., 2025).
• As a theragnostic system, through the integration of magnetic nanoparticles or gadolinium-chelating probes into collagen scaffolds, enabling non-invasive monitoring of the vector and degradation processes via magnetic resonance imaging (Guzdek et al., 2025).
• For migration inhibition, using collagen hydrogels cross-linked with specific agents (e.g., 8S-StarPEG) to increase matrix viscosity and stability, mechanically restricting tumor cell migration (Kaphle et al., 2019).

Moreover, these natural biomaterials differ significantly in terms of physicochemical properties and drug delivery performance. For example, gelatin and collagen promote enhanced cell-material interactions but are characterized by a fast degradation and weak mechanical stability; in contrast alginate provides strong structural stability but lacks intrinsic bioactivity. Hence, the selection of the a specific biomaterial should be guided by the application within the context of GBM.

2.1.4 Self-assembled peptides

Another key class of biomaterials is represented by self-assembled peptides which have gained considerable attention due to their biocompatibility, versatility, and flexibility to design (Zhao et al., 2021). Peptides are composed of amino acids linked by covalent bonds and can spontaneously organize into ordered nanostructures (Levin et al., 2020; Bellavita et al., 2022; Saviano et al., 2023). Peptide self-assembly is driven by forces such as electrostatic interactions, hydrogen bonding, π–π stacking, van der Waals forces, and hydrophobic interactions, and is strongly influenced by the peptide’s secondary structure (Zhang, 2017). These factors control the molecular organization and drive the formation of diverse nanostructures, such as micelles, nanoparticles, and nanofibers, each characterized by specific shapes, morphologies, and dimensions. Importantly, the self-assembly process is dynamic and reversible, as it can be modulated by external environmental factors including pH, temperature, enzymatic activity, ionic strength, and solvent conditions.

An abundant class of self-assembled peptides are peptide amphiphiles (PAs) formed by both a hydrophobic tail (e.g., alkyl chain tails) and hydrophilic region represented by hydrophilic amino acids (e.g., arginine, aspartic acid); both regions are essential for promoting the self-assembly process (Zhao et al., 2021). The alkyl chain tail can be introduced in N- or C-termini of the peptide sequence, while bioactive peptides such as cell-penetrating peptides, targeting peptides, and drugs can be linked to the hydrophilic region.

Owing to their amphiphilic nature, PAs can self-assemble into a variety of nanostructures, including nanovesicles, nanotubes, nanofibers, and hydrogels, each characterized by distinct morphologies and physicochemical properties. These nanostructures can be further functionalized with bioactive molecules or therapeutic agents, enabling controlled and stimuli-responsive drug release in response to physiological conditions or specific biological triggers at the target site. Consequently, PA-based nanocarriers offer significant advantages for the delivery of hydrophobic drugs, nucleic acids, peptide therapeutics, and vaccines, but their clinical translation is still limited by their in vivo stability and scalability.

For example, Wang et al., used a dehydropeptide (DDP) monomer (Boc-(Z)C^α,β-ΔPhe-Gly-NHMe for the construction of a peptide-based nanofiber (Wang et al., 2022). The authors loaded TMZ inside the nanofiber by exploiting intermolecular hydrogen bonds between DDP and the drug. The in vitro cell viability assays demonstrated that TMZ-loaded nanofiber exhibited significantly enhanced antitumor activity against U118-MG cells (IC₅₀ = 552.1 μM) compared with free TMZ (IC₅₀ = 1980.1 μM). This improved efficacy was likely attributable to a greater cellular uptake of TMZ when delivered through the nanofiber, resulting in increased intracellular drug accumulation relative to direct administration of the free drug.

2.1.5 Phospholipids

Phospholipids belong to the various classes of biomaterials used in pharmaceutical applications as drug delivery systems (Gan et al., 2024). They are characterized by a polar head linked to a glycerol or sphingosine backbone, coupled with one or more hydrophobic tails of fatty acids (Drescher and van Hoogevest, 2020). Phospholipids can be derived from both natural and synthetic sources. In nature, they are generally extracted from plant sources, such as soybean, sunflower, or rapeseed oils. However, plant sources are not the only ones; phospholipids can be obtained from animal-derived materials as well, such as egg yolk or brain tissue. Among the most common phospholipids are phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin (Baer, 1965). Their composition is not fixed since the relative amounts of phospholipids and their fatty acid profile can vary depending on the source (Eibl, 1980).

Liposomes are among the phospholipid-based delivery systems and can be classified based on their characteristics (Gan et al., 2024). They are distinguished into small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), and multilamellar vesicles (MLVs) (Wang, 2025). One of the main limitations of these systems, however, lies in their low half-life. To overcome this problem, they have been engineered by adding polyethylene glycol (PEG) units to the polar heads, creating a steric barrier capable of repelling opsonins and increasing the circulatory half-life from a few minutes to several hours. (Di Filippo et al., 2021). Additionally, these liposomal systems present several limitations including rapid clearance by phagocytosis, potential immunogenicity, and variability to BBB crossing. However, their highly tunable surface enables diverse functionalization strategies that can be exploited to enhance BBB crossing (Gan et al., 2024). A notable example in GBM therapy is the study by Lakkadwala et al., who developed a dual-functionalized liposomal system, simultaneously administering Doxorubicin (DOX) and Erlotinib (ERLO). Liposomes were prepared using the thin-film hydration method, and surface modification with transferrin (Tf) and the cell-penetrating peptide TAT was achieved via post-insertion. In vivo biodistribution studies demonstrated that dual-functionalized Tf-CPP liposomes achieved more than a 10-fold increase in brain accumulation of doxorubicin and a 2.7-fold increase for erlotinib compared to free drugs (Lakkadwala et al., 2020). The enhanced delivery across the BBB was attributed to the synergistic combination of receptor-mediated transcytosis (via transferrin receptor targeting) and adsorptive-mediated transcytosis (via CPP), resulting in improved antitumor efficacy in both in vitro brain tumor models and in vivo studies.

2.2 Synthetic biomaterials

Synthetic biomaterials represent a fundamental class within the field of biomaterial-based delivery systems (Wang, 2025). This is mainly due to their peculiar properties, such as the ability to combine therapeutic and imaging functionalities within a single platform (Herdiana et al., 2021). Compared to natural biomaterials, their physicochemical properties, including reproducibility and scalability, can be controlled and modulated for a potential clinical translation. Among synthetic biomaterials, polymers have emerged since have a high ability to control drug release, guaranteeing also the protection from degradation. This high level of tunability further enables targeted delivery strategies, ultimately enhancing the overall therapeutic response (Satchanska et al., 2024). Below, some types of synthetic polymers and other materials widely used in this field are described.

2.2.1 Poly-lactic acid (PLA)

Poly-lactic acid (PLA) is one of the most well-known and widely used synthetic polymers in the biomedical field, mainly due to its characteristics such as biocompatibility and biodegradability (Polonio-Alcala et al., 2019). One relevant application of PLA relies on its ability to encapsulate therapeutic agents, ensuring sustained release and extended circulation (Ramalho et al., 2023; Liu et al., 2024), but its clinical use remains uncertain due to tumour environment, BBB integrity, and immune response.

In the GBM context, PLA-based NPs have shown great promise in delivering chemotherapeutic agents. For example, Wang et al. developed active-targeting and stimulus-responsive micelles designed to overcome both the BBB and multi-drug resistance (Wang et al., 2023). Using the thin-film hydration method, polymeric micelles Fis-DOX/cRGD-NPs were loaded with fisetin and doxorubicin into their hydrophobic core. Results from in vitro studies demonstrated that the micelles crossed the BBB, and fisetin promoted cellular uptake of doxorubicin inducing G2/M phase arrest and activating apoptosis.

Furthermore, the PLA-based biomaterial was also used for the construction of a biocompatible nanofibers loaded with TMZ and Oleuropein for a local GBM treatment in post-surgery (Ercelik et al., 2023). Ercelik and co-workers designed this PLA-nanofiber for achieving a controlled release of both drugs in the GBM site that increased over 120 h by suppressing completely the proliferation of GBM cells.

2.2.2 Poly (lactic-co-glycolic acid) (PLGA)

Poly (lactic-co-glycolic acid) (PLGA) belongs to the class of synthetic materials and is obtained through the copolymerization of lactic acid and glycolic acid. The metabolites resulting from its degradation (lactate and glycolate) are naturally present in the human body, making this polymer an excellent biomaterial (Fonseca et al., 2015; R et al., 2018). The PLGA-based formulations demonstrated remarkable capability in delivering chemotherapeutic agents to target sites, including the central nervous system (R et al., 2018).

PLGA-based nanoparticles (NPs) are outstanding candidates for this approach (Maeda et al., 2001). In GBM treatment, PLGA-NPs are specifically engineered to cross the restrictive environment of the blood-brain barrier (BBB). A significant advancement is represented by the development of dual-drug delivery systems, such as the PLGA-mPEG nanoparticles recently designed to co-encapsulate TMZ and Ligustilide (LIG) (Ke et al., 2025). In this study, Ke et al. demonstrated that PEGylated PLGA nanoparticles improved both the storage stability and pharmacokinetics of encapsulated drugs. Nanoencapsulation increased TMZ half-life by 1.62-fold, protecting it from rapid degradation. Additionally, LIG within the PLGA matrix inhibited P-glycoprotein and modulated tight-junction proteins, enhancing BBB permeability and resulting in significantly higher cytotoxicity against U251 and C6 glioma cells compared to conventional treatments (Ke et al., 2025).

2.2.3 Poly (ε-caprolactone) (PCL)

Poly (ε-caprolactone) (PCL) is another relevant synthetic polymer, obtained through ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) (Fonseca et al., 2015). One of its distinctive features is its slow in vivo degradation, making it suitable for the preparation of drug delivery systems with prolonged release profiles (Fonseca et al., 2015). PCL plays a crucial role in the development of nanomaterials for its ability to encapsulate hydrophobic drugs and its potential to be functionalized with targeting peptides (Milane et al., 2011). By protecting drugs from degradation and facilitating their release, PCL-based systems confirm themselves as a versatile platform for improving therapeutic outcomes (Nwazojie et al., 2023).

One advantage related to the use of PCL-based nanosystems includes PCL degradation profile; unlike other more common biomaterials, its breakdown products are notably less acidic, and this tends to keep the local microenvironment less toxic, also limiting inflammatory responses (Fonseca et al., 2015). Its mechanical properties, combined with its high drug permeability, make PCL an excellent biomaterial for pharmaceutical applications and for obtaining drug-delivery systems (Bhadran et al., 2023). In a study performed by Varan et al., PCL was used for post-operative delivery of Docetaxel (DOC) in glioma treatment (Varan and Bilensoy, 2017). The authors prepared PEGylated PCL-based nanoparticles (mePEG-PCL) and coated with chitosan (CS) to improve their cellular internalization. (Varan and Bilensoy, 2017) (Varan and Bilensoy, 2017). These nanoparticles were incorporated into a bioadhesive film made of hydroxypropyl cellulose (HpC) and they achieved a sustained release of the Docetaxel over 48 h (Varan and Bilensoy, 2017). From a therapeutic perspective, the CS-mePEG-PCL nanoparticles demonstrated superior cytotoxicity against RG2 glioma cells compared to the free drug solution, a result attributed to both the enhanced uptake of cationic particles and the intrinsic antitumor activity of chitosan.

Beyond localized delivery, PCL-based nanocarriers are used to overcome the BBB via systemic administration. For example, Xin et al. have developed PEG-PCL nanoparticles decorated with the Angiopep-2 targeting he low-density lipoprotein receptor-related protein (LRP), which is overexpressed on both the BBB and glioma cells (Xin et al., 2012). Indeed, the authors demonstrated that these nanoparticles loaded with paclitaxel (PTX) were able to cross effectively the BBB through a receptor-mediated mechanism, and this result was demonstrated both in vitro and in vivo studies.

2.3 Biomaterials functionalized with therapeutic agents

The following sections provide a comprehensive overview of biomaterials functionalized with therapeutic agents for GBM treatment, highlighting their composition, delivery strategies, and preclinical and clinical outcomes (Figure 4). A comparative overview of the main biomaterial-based delivery systems discussed in this review is summarized in Table 1.

TABLE 1. Comparative overview of biomaterial-based systems for GBM treatment.

2.3.1 Chemotherapeutic-functionalized biomaterials

Temozolomide (TMZ) remains the standard chemotherapeutic agent for GBM owing to its oral bioavailability and partial ability to cross the BBB (Jezierzanski et al., 2024). However, its therapeutic efficacy is strongly influenced by the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter which represents a major mechanism of resistance in cancer cells. This limitation can be overcome using biomaterials engineered for the co-delivery of MGMT inhibitors or gene-silencing agents to downregulate MGMT expression. Additionally, the development of ad -hoc biomaterial-based delivery strategies can improve TMZ stability, tumor localization, and intratumoral exposure while reducing off-target toxicity (Pourmadadi et al., 2023).

Among synthetic polymeric platforms, PLGA and PLA are widely employed to fabricate delivery systems enable to sustain TMZ release and prolonged retention within the tumor microenvironment (Jain et al., 2016). Sayiner et al., developed TMZ-loaded PLGA and were incorporated in thermoreversible hydrogels to support controlled intracavitary release after surgical resection while preserving cytotoxic activity (Sayiner et al., 2020).

Moreover, PLGA-based carriers have also been engineered for combination therapies and active targeting, including co-delivery with bortezomib and surface functionalization with transferrin to enhance receptor-mediated uptake and BBB transport (Ramalho et al., 2023). More advanced systems integrating release control and targeting, such as HA-modified PLGA nanoparticles, displayed high encapsulation efficiency, pH-responsive release, receptor-mediated uptake, and enhanced cytotoxicity in GBM models (Roy et al., 2025). Comparable improvements have been reported for pH-responsive PEG-based micelles functionalized with tumor-targeting peptides (Miller et al., 2016).

Natural and semi-synthetic polymers are also being explored to expand the range of TMZ delivery strategies. For example, Bellavita et al., designed and developed a PAs-based nanofiber featured by high versatility and he capacity to simultaneously deliver multiple therapeutic agents. In the context of glioblastoma (GBM) treatment, the nanofiber surface was functionalized with temozolomide (TMZ) and 1,3-bromopyruvate (BrP), a glycolysis inhibitor, using an on-demand strategy to enable selective drug release at the tumor site (Bellavita et al., 2025; Be et al., 2025). Specifically, this nanofiber was composed of two structural peptides P1 and P2, each containing a hydrophobic domain consisting of nonadecanoic acid (C19) and hexa-alanine sequence, and a hydrophilic domain enriched in negatively and positively charged amino acids (Be et al., 2024). Owing to its high surface area, the nanofiber was further functionalized with the cell-penetrating peptide gH625 to facilitate BBB crossing, and with the targeting peptide falGea to promote selective binding to epidermal growth factor receptor (EGFR)-overexpressing cancer cells. The authors demonstrated that the co-delivery of TMZ and BrP resulted in approximately 80% reduction in U-87 GBM cell viability at low drug concentrations (5 μM), whereas significantly higher concentrations (200 μM) were required when the drugs were administered individually.

Moreover, chitosan-based nanoparticles and hydrogels have also attracted considerable attention due to their ability to provide sustained release, remaining mechanically compatible with brain tissue (Sarkar et al., 2025), while alginate hydrogels allow for diffusion-controlled release and can serve as 3D GBM models (Del Rocio Aguilera-Marquez et al., 2025). Hyaluronic acid (HA)-based platforms offer an additional advantage, as they can exploit the overexpression of the CD44 receptor on GBM cells to improve cellular uptake and targeting selectivity (Kasprzyk et al., 2025). In parallel, PEG-based matrices are frequently employed to improve biocompatibility, diffusion, and stability in brain tissue (Fourniols et al., 2015). Injectable PEG-DMA hydrogels, together with electrospun or photopolymerizable systems, have been shown to reduce burst release and enable prolonged TMZ delivery, resulting in significant antitumor activity in vivo (Badia-Hernandez et al., 2025).

Among chemotherapeutic drugs, Doxorubicin (DOX) is a widely used potent anthracycline with well-established anticancer activity, primarily mediated through DNA intercalation, topoisomerase II inhibition, and reactive oxygen species generation. In GBM, its clinical application is severely limited by poor BBB penetration, rapid systemic clearance, and dose-limiting cardiotoxicity, often leading to sub-therapeutic intratumoral concentrations (Nozhat et al., 2023; Madani et al., 2022). These constraints, therefore, stimulated extensive research in the development of advanced delivery systems aimed at improving tumor accumulation while reducing off-target toxicity.

Among synthetic polymeric platforms, PLGA-based nanoparticles remain extensively studied for sustained DOX release and protection from degradation, with variations in polymer composition and molecular weight allowing fine control over degradation kinetics and intratumoral retention (Maksimenko et al., 2019). PEGylation can further prolong systemic circulation and facilitate diffusion within brain tissue, especially when combined with targeting ligands or stimuli-responsive elements (Li et al., 2025). Cationic polymers such as polyethyleneimine, although intrinsically toxic, have been incorporated into multifunctional or shielded architectures to enhance cellular uptake and endosomal escape, ultimately improving DOX efficacy in resistant GBM models (Ghaferi et al., 2022). In addition, polymeric micelles and liposomes have also been optimized to facilitate transport across the BBB/BBTB and tumor penetration; notable examples include GLUT1-targeted PEG-PE micelles co-delivering DOX and curcumin, which significantly increased nuclear DOX accumulation, as well as receptor-targeted liposomal systems that enhanced apoptosis and survival in GBM models (Sarisozen et al., 2016; Han et al., 2021; Lakkadwala and Singh, 2019).

Natural and biomimetic carriers further expand DOX delivery options. Chitosan nanoparticles and hydrogels enable high drug loading and sustained release, improving cellular uptake and antitumor activity (Adiguzel et al., 2024), while alginate hydrogels provide diffusion-controlled depots suitable for post-resection implantation (Bahwal et al., 2025). Hyaluronic acid-based systems exploit CD44 overexpression for receptor-mediated uptake (Malfanti et al., 2022), and elastin-like polypeptide hydrogels have been proposed as injectable local depots reducing GBM cell viability in vitro (Dragojevic et al., 2022). For example, Dragojevic et al., engineered elastin-like hydrogels loaded with Dox via an acid-cleavable hydrazone linker. Their biological evaluations demonstrated sustained drug release and a significant inhibition of the GBM cell proliferation.

2.3.2 Biomaterial-based delivery of tyrosine kinase inhibitors

Aberrant tyrosine kinase signaling drives GBM growth, angiogenesis, and resistance, making tyrosine kinase inhibitors (TKIs) attractive yet challenging therapeutic candidates due to limited brain penetration and efflux-mediated clearance. Biomaterial-based delivery systems have therefore been developed to improve bioavailability, brain accumulation, and therapeutic index (Brar et al., 2022). Liposomes, particularly when surface-functionalized with targeting ligands such as transferrin, have enhanced brain uptake and intracellular delivery of TKIs including erlotinib and dasatinib (Lakkadwala and Singh, 2019; Bozzuto and Molinari, 2015).

Polymeric nanoparticles based on PLGA or PEG-containing copolymers allow to achieve controlled release and mitigation of efflux mechanisms; examples include P-glycoprotein-inhibitor co-formulations to increase imatinib accumulation and aptamer-decorated carriers enabling targeted delivery of PI3K/mTOR inhibitors (Kucinska et al., 2024; Monaco et al., 2017). In addition, polymeric micelles support delivery of poorly soluble TKIs and incorporation of brain-targeting ligands, improving efficacy and reducing toxicity in orthotopic GBM models (Xu et al., 2022; Nehoff et al., 2015).

2.3.3 Biomaterials in immunotherapy

Despite transformative success in other cancers, immunotherapy has shown limited durable benefit in GBM due to an immunosuppressive microenvironment, low mutational burden, impaired antigen presentation, poor T-cell infiltration, and BBB/BBTB constraints. Therefore, biomaterial-enabled delivery has focused on enhancing local immune modulation and spatiotemporal control of immunotherapeutic signals (Abadi et al., 2021).

Nanocarriers have strengthened immune checkpoint inhibition by improving brain accumulation and local immune activation. Lipid- and polymer-based systems enabled BBB transport and delivery of immune modulators, including poly (β-L-malic acid) nano–immune conjugates functionalized with transferrin and Angiopep-2 that delivered anti-PD-1 or anti-CTLA-4 antibodies and prolonged survival in GBM models (Galstyan et al., 2019). Vaccine strategies have similarly benefited from biomaterials: implantable PLGA scaffolds loaded with tumor antigens and immune adjuvants supported sustained release, dendritic cell recruitment, and prolonged T-cell activation, improving survival (Ali et al., 2011). Biomaterials have also supported adoptive and innate immune approaches. Liposomal co-delivery of immunomodulators enhanced antitumor responses (Iturrioz-Rodriguez et al., 2021; Zhang et al., 2018), while CAR T-cell–derived exosomes emerged as a cell-free strategy retaining cytotoxicity without inhibitory checkpoints (Fu et al., 2019). Cytokine modulation has been achieved using exosomes and iron oxide nanoparticles, the latter enabling localized hyperthermia–induced immune activation (Jnaidi et al., 2020; Martinez-Boubeta et al., 2013).

Bevacizumab, the only antibody approved for GBM, has also benefited from biomaterial delivery. PLGA nanoparticles preserved antibody activity and enhanced anti-angiogenic efficacy (Sousa et al., 2017). Advanced multidrug PLGA systems co-encapsulating bevacizumab and metabolic inhibitors improved brain accumulation and survival following intranasal administration. Exosome-mediated bevacizumab delivery further enhanced BBB transport and therapeutic efficacy while maintaining antibody functionality (Chu et al., 2025).

2.3.4 Biomaterials in gene therapy

Nucleic acid therapeutics offer high molecular specificity but face key barriers such as nuclease degradation, inefficient uptake, endosomal sequestration, and limited BBB transport. Biomaterial-enabled delivery systems are therefore central to improving biodistribution, intracellular delivery, and therapeutic efficacy, particularly in preclinical studies.

siRNA. Biomaterial carriers are therefore essential to improve protection, delivery, and cytosolic release (Teng et al., 2022). Polymeric nanoparticles, particularly cationic and biodegradable systems, have enabled silencing of key GBM drivers such as STAT3, EZH2, PLK1, VEGF, and DNA damage response factors, resulting in tumor growth inhibition and radiosensitization (Linder et al., 2019; Zhou et al., 2018; Zhang et al., 2020). Lipid nanoparticles and peptide-based carriers further support systemic and intranasal delivery, while engineered exosomes provide BBB-permeable, tumor-homing platforms (Hu et al., 2022; P et al., 2020).

miRNA. The delivery faces similar barriers and has been dominated by polymeric and lipid systems (Chen et al., 2021). PLGA nanoparticles delivering anti-miR-21 or anti-miR-10b enhanced TMZ sensitivity (Ananta et al., 2015), while PEI-based and lipid formulations enabled efficient delivery of tumor-suppressive miRNAs such as miR-34a, miR-145, and miR-124, reducing stemness, resistance, and recurrence (Yang et al., 2012).

Aptamers are short single-stranded oligonucleotides acting as high-affinity ligands and have attracted growing interest as biosensors and diagnostic and therapeutic elements (Abduvakhidov and Campas, 2026; Cesarini et al., 2020; Nuzzo et al., 2020; Benigno et al., 2022; Virgilio et al., 2024). Therapeutic aptamers combine high selectivity with intrinsic bioactivity, being potential antagonists of disease-associated proteins and can also function as delivery ligands (Esposito et al., 2023; Virgilio et al., 2021; Virgilio et al., 2022). RNA aptamers such as Gint4. T and CL4 target PDGFRβ and EGFR, respectively, inhibiting GBM growth and migration (Camorani et al., 2014). Aptamer–siRNA chimeras enabled carrier-free, receptor-mediated STAT3 silencing, improving tumor inhibition and immune modulation (Esposito et al., 2018). AS1411 and EphA2-targeting aptamers further demonstrated antiproliferative activity and have been widely employed as targeting ligands for nanoparticle delivery (Cheng et al., 2016; Guo et al., 2011; Affinito et al., 2019). Aptamer–drug conjugates and stimulus-responsive designs integrate targeting with controlled release, reducing off-target toxicity (Castellani et al., 2025; Benigno et al., 2024).

3 Biomaterial-based strategies in clinic

Several biomaterials have also progressed into clinical trial evaluation phases. In most cases, these biomaterials have been used either in combination with chemotherapeutic drugs, immunotherapeutic cargoes or in implantable devices.

The clinical trial landscape of GBM has seen significant scientific enquiry with over 2000 studies. However, with a strict interest in biomaterials, the number of studies has reduced significantly. Particularly, six distinct biomaterial platforms have been investigated for GBM treatment through documented clinical trials. These include biodegradable polymers for local chemotherapy delivery (carmustine-impregnated wafers and Z-BP wafers), gadolinium-based nanoparticles for radiosensitization (AGuIX), autologous cell-based immunotherapies (IGV-001) and adipose-derived mesenchymal stem cells (Table 2).

TABLE 2. Summary of biomaterial-based platforms evaluated in clinical trials GBM, including therapeutic strategy, route of administration, and clinical phase.

Biodegradable polymer-based delivery systems represent the most direct application of biomaterials in GBM treatment. The strategy that involves the use of biodegradable polymers depend directly on material composition, degradation kinetics, and release profiles to achieve therapeutic exposure. These biopolymers are designed for implantation or localized administration to achieve sustained or controlled drug release at the tumour site while minimizing systemic exposure.

J. Rudnick et al. used Gliadel Wafers combined with dendritic cell vaccination that are implanted in the resection cavity after surgical resection in a study of 28 patients (Rudnick et al., 2020). Following surgical resection, Gliadel Wafers were placed along the resection cavity.

For all patients, the median progression-free survival was 3.6 months, while the median overall survival was 16.9 months from the start of vaccination. Overall, this combination therapy resulted to be safe, but a statistical significance was not reached between vaccine responders and non-responders.

Most clinical studies on biomaterials have demonstrated their safety and feasibility, validating material-guided release as a viable strategy in the post-surgical setting. Despite these advantages, clinical benefit remains constrained by restricted diffusion distances and in metastatic GMB tumors.

Biomaterial-based strategies often involve not only material carriers but also device-enabled delivery systems that are essential for achieving controlled distribution within the brain. One example is the implantable ultrasound system SonoCloud, developed for BBB disruption (Carpentier et al., 2024). SonoCloud has demonstrated no detectable adverse effects at acoustic pressures up to 1.1 MPa (Table 2). Notably, this consistent safety profile across different therapeutic modalities, including chemotherapy, radiosensitization, immunotherapy, and BBB disruption. These findings suggest that localized delivery approaches can effectively limit systemic toxicity, independent of the therapeutic payload.

Overall, the documented clinical trials reveal distinct therapeutic strategies across biomaterial platforms, with progression from early-phase safety studies to pivotal efficacy trials varying by development timeline. The diversity in trial designs reflects different regulatory pathways and scientific rationales. Local drug delivery platforms (e.g., gliadel wafers) demonstrate efficacy through direct tumor exposure with minimal systemic toxicity, while systemic approaches require dose-escalation to establish safety margins (AGuIX at 50–100 mg/kg). Radiosensitizers (RTs) like AGuIX achieve therapeutic concentrations in 65.5% of tumour volume through selective accumulation, whereas locally implanted wafers achieve >2 cm diffusion from implantation sites (Aubrun et al., 2025). These distinct pharmacokinetic profiles necessitate different clinical endpoints and assessment timeframes.

Additionally, Focused ultrasound–based strategies represent one of the most clinically advanced non-invasive approaches to overcoming the BBB in GBM (Hersh et al., 2022). Inducing transient, localized BBB disruption, allows these systems to enable enhanced penetration of chemotherapeutics or immunomodulatory agents that otherwise exhibit limited intracranial delivery. For example, the phase 1 clinical trial (NCT07179328) aims to use The Next-Generation Dome Helmet (FUS NG), a non-invasive MRI-guided focused ultrasound system developed at Sunnybrook Research Institute (Clinicaltrials, 2025). It is used to disrupt BBB in patients with glioblastoma during the maintenance phase of TMZ therapy. The device allows targeted BBB opening using a fixed transducer array and intravenous DEFINITY® contrast together with a drug Definity® Vial for (Perflutren Lipid Microsphere) Injectable Suspension. DEFINITY® Perflutren Injectable Microbubbles is an ultrasound contrast imaging agent that will be used for BBB opening during focused ultrasound. These microbubbles will be injected during the focused ultrasound procedure. Another similar trial (NCT05864534) used a novel implant device with nine ultrasound emitters, allowing temporary and reversible opening of the BBB to maximize brain penetration of drugs that modulate the immune system. This device is used alongside intravenous administration of anti-PD-1 antibody, balstilimab, botensilimab and liposomal doxorubicin (NCT05864534) (Kim et al., 2024). Early-phase clinical trials consistently demonstrate feasibility and acceptable safety profiles, supporting repeated BBB modulation without permanent tissue damage. Importantly, these studies highlight the role of physical biomaterial-tissue interactions rather than novel drug entities in addressing delivery constraints. However, clinical efficacy remains variable, reflecting challenges in achieving uniform drug distribution across the highly infiltrative tumor margins characteristic of glioblastoma.

Furthermore, therapeutic benefit is tightly coupled to precise spatial targeting and timing of drug administration, increasing procedural complexity (Leao et al., 2020). Despite these limitations, focused ultrasound platforms illustrate a paradigm in which biomaterial-enabled modulation of tissue barriers, rather than new cytotoxic agents, drives clinical innovation. Their integration with nanoparticles or immune-based therapies may further expand their translational relevance in future combination strategies.

Nanoparticle-based delivery strategies improve therapeutic index modifying drug pharmacokinetics and spatial distribution within the brain. Liposomal and carrier-assisted formulations evaluated in clinical trials seek to reduce systemic toxicity while enhancing tumor exposure, particularly when combined with intra-arterial (IA) administration or BBB-modulating techniques. For instance, patients which carboplatin fails, other chemotherapeutics are chosen arbitrarily from a list of agents available for IA infusion. As such, a trial (NCT06356883) has opted into the use of carboplatin, which have been combined with Caelyx, liposomal doxorubicin drug or etoposide phosphate. The liposomal formulation of doxorubicin (Caelyx) exhibits an altered pharmacokinetic profile favoring the use of this drug formulation in brain tumor treatment. A contrasting approach using AGuIX nanoparticles represents a gadolinium-based theranostic platform designed for radiosensitization in GBM treatment. These gadolinium chelated polysiloxane-based nanoparticles accumulate selectively in tumors via the Enhanced Permeability and Retention (EPR) effect and undergo rapid renal elimination (Thivat et al., 2023). The delivery method is the intravenous injection in conjunction with radiotherapy and chemotherapy. The NANO-GBM trial (NCT04881032) is a multicentre Phase I/II randomized trial testing AGuIX with radiotherapy (60 Gy) and concomitant/adjuvant temozolomide in newly diagnosed glioblastoma patients. Eligible patients have grade IV glioblastoma with incomplete resection (biopsy or partial surgery) and Karnofsky Performance Status ≥70%. The trial spans 6 sites with a target enrolment of 66 patients. AGuIX nanoparticles showed lack of treatment related toxicity with only one dose-limiting event (grade 3 lymphopenia attributed to concurrent temozolomide). However, despite encouraging preclinical findings, clinical evidence remains limited and lacks comprehensive reporting of efficacy outcomes. To date, these studies have not consistently demonstrated significant survival benefits, highlighting persistent challenges such as heterogeneous tumor perfusion and limited penetration into infiltrative tumor regions. Importantly, these trials reveal that nanoparticle delivery alone is insufficient to overcome the complex biological barriers of glioblastoma, emphasizing the need for multimodal delivery paradigms. Despite modest efficacy signals, nanoparticle approaches remain central to biomaterial-based GBM strategies, particularly as components of combination regimens incorporating physical or immune-modulatory interventions.

4 Conclusions and future perspectives

In this review, we described and summarized the most widely used natural and synthetic biomaterials and their applications in the drug delivery field for GBM treatment, highlighting both their therapeutic potential and the key limitations that still hinder clinical translation. Unfortunately, although FDA-approved drugs are effective, they cause systemic toxicity for their non-specific distribution in healthy organs and tissues, and for this reason, there is urgent need to use biomaterials to develop drug delivery systems to mitigate these side effects. In this context, biomaterials-based delivery systems offer clear advantages by enhancing drug bioavailability, solubility, stability, safety, and controlled release, thereby potentially enhancing therapeutic efficacy while minimizing off-target effects. Despite these advances, the field remains largely preclinical, and a gap persists between promising experimental outcomes and successful clinical implementation. Natural biomaterials, such as hyaluronic acid, alginate, gelatin, and collagen provide intrinsic biocompatibility and bioactivity, yet often suffer from batch variability and limited mechanical tunability. In contrast, synthetic polymers offer greater control over physicochemical properties and scalability but may raise concerns regarding long-term biocompatibility and degradation profiles. Moreover, a limited number of biomaterial-based systems successfully progress to clinical trials, often due to challenges related to their ability to overcome biological barriers such as BBB, stability, large-scale production, administration routes, and in vivo circulation.

Therefore, further research is required to rationally design, optimize, and standardize biomaterial-based delivery platforms combined with the precision medicine approaches, including patient-specific targeting, stimuli-responsive systems, and combinatorial therapies. For example, the construction of stimuli-responsive biomaterials, capable of releasing drug in response to specific tumor conditions (e.g., pH, enzyme, hypoxia), can be increase therapeutic efficacy. In addition, the incorporation of precision medicine principles could help address the issue related to the GBM heterogeneity and variability that are major contributors to therapeutic failure. Overall, the successful translation of biomaterial-based delivery systems for GBM will depend on interdisciplinary efforts bridging materials science, neuro-oncology, and regulatory science.

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Footnotes

Edited by: Simona Rapposelli, University of Pisa, Italy

Reviewed by: Purusottam Mishra, Silesian University of Technology, Poland

Şeyma Işik, Acıbadem University, Türkiye