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EURASIAN EXPERIMENT JOURNAL OF BIOLOGICAL SCIENCES (EEJBS)

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Crossing Biological Barriers: Nanoscale Strategies for

ABSTRACT
Brain tumors remain among the most challenging malignancies to treat due to the presence of complex
biological barriers, particularly the blood-brain barrier (BBB) and blood-tumor barrier (BTB), which restrict the
entry of therapeutic agents. Traditional chemotherapies often fail to achieve adequate drug concentrations at
the tumor site, resulting in suboptimal therapeutic outcomes and systemic toxicity. Nanoscale drug delivery
systems have emerged as promising tools to overcome these limitations by enhancing drug solubility, stability,
and site-specific delivery. This review explores the physiological and structural challenges posed by the BBB
and BTB and highlights the latest advancements in nanotechnology-based strategies designed to surmount
these barriers. Key nanocarrier platforms, including liposomes, polymeric nanoparticles, dendrimers, and
exosomes, are critically examined for their potential in targeting brain tumors. Furthermore, this review
discusses active and passive targeting mechanisms, stimuli-responsive delivery systems, and the integration of
theranostics for simultaneous imaging and therapy. Finally, the review considers clinical translation challenges
and future perspectives for nanoscale strategies in neuro-oncology.
Keywords: Blood-brain barrier, Brain tumors, Nanocarriers, Drug delivery, Targeted therapy

INTRODUCTION
Brain tumors, whether primary (originating in the brain) or metastatic (originating elsewhere and spreading to
the brain), remain among the most devastating forms of cancer[1]. Despite progress in oncology, these tumors
are associated with high morbidity and mortality due to the unique challenges presented by the central nervous
system (CNS) environment. A primary barrier to effective therapy is the presence of tightly regulated
physiological barriers, particularly the blood-brain barrier (BBB), which acts as a selective shield between
systemic circulation and the brain[2, 3]. This complex structure comprises endothelial cells with tight junctions,
supported by pericytes, astrocytic end-feet, and a basement membrane. While essential for protecting the brain
from toxins and pathogens, the BBB also inadvertently hinders the entry of many therapeutic agents, including
up to 98% of small-molecule drugs and nearly all macromolecules, thus complicating drug delivery strategies
for brain tumors[3–5].
The blood-tumor barrier (BTB), which forms in tumor-affected regions, is typically more permeable than the
intact BBB due to abnormal angiogenesis and leaky vasculature. However, this permeability is often inconsistent
and heterogeneous, varying with tumor subtype, grade, and anatomical location[6, 7]. This irregularity leads
to uneven drug distribution, making it difficult to achieve therapeutic concentrations across the entire tumor
mass and contributing to therapeutic failure and tumor relapse. As a result, conventional treatment strategies
such as surgical resection, radiation therapy, and systemic chemotherapy have shown limited efficacy, especially
in infiltrative or inoperable tumors such as glioblastoma multiforme[8, 9].
In response to these challenges, nanotechnology has emerged as a promising platform for improving drug
delivery across the BBB and BTB. Nanocarriers—engineered particles typically ranging from 1 to 200
nanometers—are being developed to exploit both passive and active targeting mechanisms to enhance
therapeutic delivery[10]. Passive targeting takes advantage of the enhanced permeability and retention (EPR)
effect in tumor vasculature, while active targeting employs ligands or antibodies that recognize tumor-specific
markers to enhance binding and uptake by tumor cells[11, 12]. These strategies can improve the
pharmacokinetic and pharmacodynamic profiles of anticancer drugs, increase their accumulation within the
tumor microenvironment, and reduce off-target toxicity in healthy tissues[13].

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Furthermore, functionalized nanocarriers can be designed to respond to specific stimuli—such as pH, enzymes,
or temperature—within the tumor milieu, triggering controlled and localized drug release[14, 15]. Innovations
in nanomedicine also include biomimetic systems that cloak nanoparticles in cell membranes to evade immune
detection and increase circulation time. Collectively, these advances are shifting the paradigm of brain tumor
therapy from systemic and non-specific approaches to precision-guided, targeted interventions[14, 16]. This
review looks into the multifactorial barriers that hinder therapeutic delivery in brain tumors and critically
assesses the array of nanoscale strategies being developed to circumvent these barriers. By highlighting recent
breakthroughs and evaluating current limitations, we aim to provide an integrative overview of how Page | 79
nanomedicine can be leveraged for precision neuro-oncology, paving the way for improved treatment outcomes
and personalized therapeutic regimens.
2. The Challenge of Biological Barriers in Brain Tumor Therapy
2.1 The Blood-Brain Barrier (BBB): The blood-brain barrier (BBB) represents a highly specialized and tightly
regulated vascular interface that separates the systemic circulation from the central nervous system (CNS)[17].
This barrier is composed primarily of non-fenestrated endothelial cells that are interconnected by tight
junctions, creating a physical blockade that strictly limits paracellular transport. Supporting this structural
integrity are pericytes embedded in the basement membrane, astrocytic end-feet enveloping the capillaries, and
various transporters and enzymes that regulate molecular trafficking[18]. The primary physiological role of
the BBB is to maintain CNS homeostasis by selectively permitting the passage of essential nutrients while
preventing the entry of harmful substances, including pathogens, toxins, and xenobiotics[19].
However, in the context of brain tumor therapy, the very features that make the BBB protective also make it a
formidable obstacle[20]. The barrier restricts nearly all large therapeutic molecules and up to 98% of small-
molecule drugs from entering the brain parenchyma. Even promising chemotherapeutic agents with
demonstrated efficacy against tumor cells in vitro often fail in vivo due to inadequate penetration across the
BBB[21]. Moreover, active efflux transporters such as P-glycoprotein and multidrug resistance proteins further
reduce drug accumulation by actively pumping therapeutic agents out of the brain endothelial cells back into
the bloodstream[22].
In the setting of malignant brain tumors, the integrity of the BBB can be partially disrupted due to tumor-
induced angiogenesis and inflammatory responses. Nevertheless, this disruption is often limited and
inconsistent, failing to provide sufficient permeability across the entire tumor mass[23]. Additionally, the
surrounding normal brain tissue maintains an intact BBB, protecting areas where infiltrative tumor cells may
reside, thus shielding them from systemic therapies[23]. As a result, the BBB remains a critical bottleneck in
the successful treatment of brain tumors, necessitating the development of innovative strategies to enhance drug
penetration without compromising overall CNS function[24, 25].
2.2 The Blood-Tumor Barrier (BTB)
While the BBB presents a major hurdle in healthy brain tissue, brain tumors themselves often induce the
formation of a blood-tumor barrier (BTB), which arises due to pathological neovascularization and vascular
remodeling[26]. Unlike the tight and continuous structure of the BBB, the BTB is characterized by leaky,
irregular vasculature with disrupted tight junctions and increased fenestrations[27]. This leaky nature has led
to the idea that the BTB might be exploited for enhanced drug delivery through passive diffusion or the
enhanced permeability and retention (EPR) effect. However, this apparent advantage is often negated by the
heterogeneous nature of BTB permeability. Studies have shown that drug permeability within tumors varies
significantly depending on tumor type, grade, and intratumoral location[28, 29]. For instance, the core of a
glioblastoma may demonstrate relatively high permeability, while the infiltrative margins exhibit much lower
permeability due to retained BBB features. This spatial inconsistency results in uneven drug distribution,
creating sanctuaries where tumor cells can evade therapy and eventually lead to recurrence.
Furthermore, the abnormal architecture of tumor blood vessels within the BTB contributes to high interstitial
fluid pressure, sluggish blood flow, and compromised lymphatic drainage, all of which impair effective drug
transport and retention[30]. These physiological aberrations also affect nanoparticle distribution, potentially
limiting the therapeutic window. Additionally, the BTB is influenced by dynamic factors such as hypoxia,
inflammation, and immune cell infiltration, further complicating drug delivery[30].
The variability of the BTB underscores the necessity for drug delivery systems that can adapt to these spatial
and temporal inconsistencies. Advanced nanocarrier platforms that incorporate tumor-specific ligands,
responsiveness to tumor microenvironmental stimuli (e.g., acidic pH, proteolytic enzymes), and the ability to
penetrate deep into tumor tissue are currently under investigation[31]. A detailed understanding of the BTB’s
biophysical and biochemical properties is essential for the rational design of such systems[31]. Therefore,
overcoming the challenges posed by both the BBB and the BTB requires a multifaceted approach integrating
nanotechnology, molecular targeting, and systems biology for improved therapeutic success in brain tumor
management.

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3. Nanoscale Drug Delivery Platforms
3.1 Liposomes
Liposomes are spherical vesicles composed of one or more phospholipid bilayers surrounding an aqueous
core[32–34]. Their structure allows for the simultaneous encapsulation of both hydrophilic drugs (within the
aqueous interior) and lipophilic drugs (within the lipid bilayer). Due to their biocompatibility and ability to
reduce systemic toxicity, liposomes are widely used in nanomedicine[35–37]. The surface of liposomes can be
modified through PEGylation, adding polyethylene glycol chains to improve circulation time by reducing
opsonization and uptake by the mononuclear phagocyte system (MPS)[38]. Furthermore, liposomes can be Page | 80
functionalized with targeting moieties such as transferrin, folic acid, or antibodies to facilitate receptor-mediated
transport across the blood-brain barrier (BBB). These targeted liposomes can enhance drug accumulation in
brain tumor tissues through active transport mechanisms. Clinically approved formulations like Doxil have
paved the way for newer liposomal systems undergoing evaluation for glioblastoma, offering promise for more
effective and less toxic brain cancer therapies.
3.2 Polymeric Nanoparticles
Polymeric nanoparticles (PNPs) are solid colloidal particles typically ranging from 10 to 1000 nanometers in
size and are fabricated from biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA), chitosan, and
polyethylene glycol (PEG)-based copolymers[39–42]. These nanoparticles offer several advantages, including
the ability to fine-tune drug release profiles and surface properties. PNPs can encapsulate a variety of therapeutic
agents and release them in a controlled manner, either through passive diffusion or environmental stimuli like
pH changes or enzymatic degradation. In the context of brain tumor therapy, their size and surface chemistry
can be optimized to enhance penetration across the BBB. Moreover, their surfaces can be functionalized with
ligands to actively target tumor-associated receptors, improving specificity and reducing off-target effects[40].
Their excellent biocompatibility, low toxicity, and ease of large-scale production make polymeric nanoparticles
promising candidates for clinical translation in the treatment of gliomas and other central nervous system
malignancies.
3.3 Dendrimers
Dendrimers are highly branched, monodisperse macromolecules that exhibit a tree-like architecture with
multiple generations extending from a central core[43]. This unique structural design offers abundant terminal
functional groups for drug conjugation, surface modification, or targeting ligand attachment. Dendrimers such
as poly(amidoamine) (PAMAM) are widely explored for drug delivery because they can encapsulate therapeutic
molecules within their interior cavities or chemically attach them to surface groups[44]. Their nanometric size
and uniformity make them suitable for crossing the BBB, especially when further functionalized with
polyethylene glycol (PEG), antibodies, or peptides[45]. These modifications improve circulation time and
targeting specificity, minimizing off-target accumulation. Dendrimers are also capable of theranostic
applications, combining therapy and diagnostics by co-delivering imaging agents and drugs in a single
platform[45]. Their highly controlled architecture allows for precise engineering, offering versatility in
developing multifunctional nanocarriers tailored for personalized treatment of brain tumors, including
glioblastoma and metastatic brain lesions.
3.4 Inorganic and Hybrid Nanoparticles: Inorganic and hybrid nanoparticles integrate metal or mineral
components with organic materials to exploit their unique physical and chemical properties for drug delivery
and imaging[46, 47]. Examples include gold nanoparticles (AuNPs), which exhibit strong surface plasmon
resonance useful in photothermal therapy; iron oxide nanoparticles, which provide contrast in magnetic
resonance imaging (MRI) and magnetic targeting; and mesoporous silica nanoparticles (MSNs), which offer
high surface area and tunable pore sizes for drug loading[46, 48, 49]. These nanoparticles can be further
hybridized with polymers or lipids to improve biocompatibility and functionalization potential. In brain tumor
therapy, these platforms are explored for targeted delivery and real-time imaging to guide surgical resection or
monitor therapeutic efficacy[50]. However, while their multifunctionality is attractive, concerns remain about
their long-term safety, biodegradability, and accumulation in tissues. Thorough investigations into their
pharmacokinetics, clearance, and toxicity profiles are essential before they can be safely integrated into routine
clinical applications for central nervous system cancers.
3.5 Extracellular Vesicles and Exosomes: Extracellular vesicles (EVs), particularly exosomes, are nanosized
(30–150 nm) lipid bilayer-enclosed particles naturally secreted by cells for intercellular communication[51–53].
They transport proteins, lipids, and nucleic acids, and possess innate capabilities to traverse biological barriers
such as the BBB. Their endogenous origin provides superior biocompatibility, low immunogenicity, and
extended circulation, making them attractive vehicles for drug delivery. Exosomes can be isolated from various
biological fluids and engineered to carry therapeutic agents, including small molecules, siRNAs, and CRISPR
components. Surface modifications, such as ligand conjugation or genetic engineering of parental cells, can
enhance their targeting to tumor tissues. In brain tumor applications, engineered exosomes are being explored
for delivering chemotherapeutics or genetic payloads to glioblastoma cells.[54–56] Their capacity to mimic

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natural cellular communication mechanisms offers a promising, minimally invasive approach to personalized
nanomedicine. However, challenges such as scalable production, efficient drug loading, and standardization of
isolation techniques need to be addressed for clinical translation.
4. Mechanisms for Crossing the BBB
4.1 Passive Targeting via EPR Effect: The Enhanced Permeability and Retention (EPR) effect refers to the
tendency of nanoparticles to accumulate in tumor tissues due to the leaky vasculature and impaired lymphatic
drainage typical of many tumors[57]. This passive targeting mechanism has been widely used in solid tumor
therapy to enhance drug concentration at the tumor site. However, the EPR effect in brain tumors is relatively Page | 81
limited compared to peripheral tumors[57, 58]. The presence of the highly selective BBB restricts passive
diffusion of most macromolecules and nanocarriers. Nonetheless, in glioblastoma and other high-grade brain
tumors, regions of the BBB may become partially disrupted, permitting some degree of nanoparticle
accumulation via the EPR effect[58]. Despite this, the heterogeneous and incomplete nature of BBB disruption
poses significant limitations for relying solely on passive targeting. As a result, passive accumulation through
the EPR effect often needs to be supplemented with active targeting strategies or stimuli-responsive systems to
achieve therapeutic concentrations in brain tumor tissues.
4.2 Active Targeting Strategies: Active targeting enhances nanoparticle delivery across the BBB and into
tumor cells by functionalizing the nanocarrier surface with ligands that bind specific receptors on endothelial or
tumor cells[59]. These ligands include transferrin, lactoferrin, folic acid, peptides (e.g., RGD), and antibodies
against overexpressed surface markers. Upon binding to their receptors, the nanoparticle-ligand complex is
internalized via receptor-mediated endocytosis or transcytosis, allowing the therapeutic payload to cross the
BBB efficiently. For example, transferrin receptor-targeting nanoparticles have shown promise in preclinical
models of glioma by improving drug accumulation in the brain. Similarly, insulin or integrin-targeted systems
exploit naturally occurring transport mechanisms to ferry drugs across endothelial barriers[60]. This strategy
not only increases specificity and uptake but also minimizes off-target side effects and systemic toxicity. Active
targeting remains a cornerstone of precision nanomedicine, particularly for brain tumors where traditional drug
delivery methods are hindered by the restrictive and protective nature of the BBB.
4.3 Stimuli-Responsive Delivery Systems: Stimuli-responsive delivery systems are intelligent nanocarriers
designed to release their therapeutic cargo in response to specific internal or external triggers[14, 61, 62]. In
the context of brain tumors, internal stimuli such as acidic pH, elevated redox potential, overexpressed enzymes,
or hypoxia within the tumor microenvironment can be exploited for controlled drug release. For example, pH-
sensitive nanoparticles can remain stable in the bloodstream (pH ~7.4) but undergo structural changes in the
acidic tumor milieu (pH ~6.5–6.8), triggering drug release specifically at the tumor site. Similarly, redox-
sensitive systems can respond to high intracellular glutathione concentrations in cancer cells to release
chemotherapeutics[63]. External stimuli such as heat, light, or magnetic fields can also be applied to trigger
release from thermosensitive, photosensitive, or magnetically-responsive carriers. These smart delivery systems
enhance therapeutic efficacy while reducing off-target toxicity. Their integration into brain tumor treatment
strategies holds great promise for overcoming the challenges of delivering potent agents across the BBB with
spatial and temporal precision.
5. Theranostic Nanomedicine and Imaging-Guided Therapy
Theranostic nanoparticles represent a cutting-edge advancement in nanomedicine by integrating diagnostic and
therapeutic functionalities into a single platform[64, 65]. This dual capability allows for simultaneous disease
imaging and targeted drug delivery, revolutionizing the way clinicians monitor and treat diseases, particularly
cancer. By enabling real-time tracking of the biodistribution of therapeutic agents and assessment of treatment
efficacy, theranostic nanoparticles can significantly enhance treatment personalization and responsiveness.
Several classes of nanoparticles have been explored for theranostic applications. Magnetic nanoparticles, such
as superparamagnetic iron oxide nanoparticles (SPIONs), serve as contrast agents in magnetic resonance
imaging (MRI) while also being capable of delivering drugs or mediating hyperthermia therapy[66, 67].
Quantum dots, owing to their unique optical properties, are used in fluorescence imaging and can be conjugated
with therapeutic molecules for targeted delivery. Gold nanoshells and nanorods, known for their tunable surface
plasmon resonance, can absorb near-infrared light and convert it into heat, enabling both photothermal therapy
and imaging.
The integration of these imaging modalities with targeted therapy helps improve treatment precision by
ensuring drugs are delivered specifically to diseased tissues while minimizing off-target effects. This reduces
systemic toxicity and enhances therapeutic outcomes. Furthermore, real-time imaging allows clinicians to assess
whether the therapeutic agent has reached its intended target and how the disease is responding to
treatment[68]. If necessary, treatment regimens can be rapidly adjusted, providing a level of adaptability not
possible with traditional methods.
In addition to oncology, theranostic nanoparticles are being studied for use in cardiovascular diseases,
neurodegenerative disorders, and infectious diseases[69]. As research progresses, improvements in

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biocompatibility, targeting specificity, and imaging sensitivity will continue to drive the clinical translation of
theranostic nanotechnologies, making them a vital component of future precision medicine strategies.
6. Clinical Translation and Challenges
Despite promising preclinical results, clinical translation of nanomedicine for brain tumors faces significant
challenges. These include manufacturing scale-up, regulatory hurdles, reproducibility, immune response, and
long-term safety. Furthermore, inter-patient variability in BBB integrity and tumor biology complicates
treatment standardization. Clinical trials such as those involving nanoliposomal irinotecan or transferrin-
modified nanoparticles have shown potential but require further validation. Page | 82
7. Future Perspectives
The future of nanoscale brain tumor therapy lies in multi-functional, smart nanoparticles that integrate
targeting, stimuli-responsiveness, and real-time feedback. Advances in artificial intelligence, microfluidic
screening models, and precision medicine will accelerate the optimization of nanoparticle formulations.
Personalized nanomedicine approaches, leveraging patient-specific tumor profiles, hold the potential to
revolutionize neuro-oncology and overcome the current limitations of conventional treatments.
CONCLUSION
Crossing the BBB remains one of the greatest hurdles in brain tumor therapy. Nanoscale drug delivery systems
offer a promising avenue for circumventing this challenge by enhancing the delivery, specificity, and safety of
therapeutic agents. Continued interdisciplinary collaboration between nanotechnology, neuroscience, oncology,
and pharmacology will be critical for translating these innovative platforms into effective clinical therapies for
brain tumor patients.
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