ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ
Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diagnoses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques, chemotherapy, targeted therapies, and immun...
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| Date: | 2026 |
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| Pages: | 81-97 |
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Experimental Oncology| _version_ | 1874183250774065152 |
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| author | Seifollahnezhad , Gheysar Erdağ, Berrin |
| author_facet | Seifollahnezhad , Gheysar Erdağ, Berrin |
| author_institution_txt_mv | [
{
"author": "Gheysar Seifollahnezhad ",
"institution": "Molecular Medicine, Istanbul Aydın University, Istanbul, Türkiye",
"orcid": "0009-0001-8605-0249"
},
{
"author": "Berrin Erdağ",
"institution": "Department of Basic Medical Sciences, Medical Biology Division, Istanbul Aydın University, Istanbul, Türkiye",
"orcid": ""
}
] |
| author_orcid_str_mv | 0009-0001-8605-0249 |
| author_sort | Seifollahnezhad , Gheysar |
| baseUrl_str | https://exp-oncology.com.ua/index.php/Exp/oai |
| collection | OJS |
| container_end_page | 97 |
| container_issue | 2 |
| container_start_page | 81 |
| container_title | Експериментальна онкологія |
| container_volume | 48 |
| datestamp_date | 2026-08-21T12:36:20Z |
| description | Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diagnoses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, long-term survival rates remain unsatisfactory, underscoring the need for innovative, molecularly driven approaches. SiRNA has emerged as a promising gene-silencing tool capable of selectively downregulating oncogenic drivers and pathways associated with resistance via RNA interference. Preclinical studies using GC models demonstrate promising biological activity following siRNA-mediated suppression of various molecular targets — including CD44v6, Rac1, and ZNRD1—leading to reduced cell proliferation, inhibited migration and invasion, enhanced apoptosis, and increased chemosensitivity. However, the successful translation of siRNA-based strategies into clinical practice is fundamentally reliant on the development of efficient and safe delivery systems. Recent advancements in nanotechnology have enabled the development of multifunctional nanocarriers, including lipid-based nanoparticles, peptide-based systems, chitosanderived platforms, exosome-mimetic vesicles, layer-by-layer architectures, and stimuli-responsive theranostic nanoparticles. These engineered platforms are designed to enhance siRNA stability, improve tumor targeting, facilitate intracellular trafficking, and promote endosomal escape while minimizing off-target effects and immune activation. Preclinical findings suggest significant biological potential; however, additional research is required to address issues concerning biodistribution, safety, scalability, and regulatory standardization before clinical application. Overall, siRNA-based strategies may play a crucial role in the future development of precision-oriented therapeutic frameworks in GC research. Importantly, this review emphasizes the integration of molecular target selection with delivery system design in a GC-specific context. By systematically linking validated siRNA targets with corresponding nanocarrier strategies, this work provides a more application-oriented and translationally relevant perspective that is not typically addressed in conventional RNA interference or nanocarrier-focused reviews. |
| doi_str_mv | 10.15407/exp-oncology.2026.02.081 |
| first_indexed | 2026-08-22T01:00:30Z |
| format | Article |
| fulltext |
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 81
https://doi.org/10.15407/exp-oncology.2026.02.081
Gheysar Seifollahnezhad 1, *, Berrin Erdağ 2, 3
1 Molecular Medicine, Istanbul Aydın University, Istanbul, Türkiye
2 Department of Basic Medical Sciences, Medical Biology Division,
Istanbul Aydın University, Istanbul, Türkiye
3 Senbio Biotechnology LTD, Istanbul, Türkiye
* Correspondence: E-mail: gheysar.seyfolahnezhad@gmail.com
THERAPEUTIC ROLE OF siRNA
IN GASTRIC CANCER: GENE SILENCING
MECHANISMS AND NANOCARRIER-BASED
DELIVERY STRATEGIES
Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diag-
noses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques,
chemotherapy, targeted therapies, and immunotherapy, long-term survival rates remain unsatisfactory, underscoring the need
for innovative, molecularly driven approaches. SiRNA has emerged as a promising gene-silencing tool capable of selectively
downregulating oncogenic drivers and pathways associated with resistance via RNA interference. Preclinical studies using GC
models demonstrate promising biological activity following siRNA-mediated suppression of various molecular targets — in-
cluding CD44v6, Rac1, and ZNRD1—leading to reduced cell proliferation, inhibited migration and invasion, enhanced apop-
tosis, and increased chemosensitivity. However, the successful translation of siRNA-based strategies into clinical practice is fun-
damentally reliant on the development of efficient and safe delivery systems. Recent advancements in nanotechnology have en-
abled the development of multifunctional nanocarriers, including lipid-based nanoparticles, peptide-based systems, chitosan-
derived platforms, exosome-mimetic vesicles, layer-by-layer architectures, and stimuli-responsive theranostic nanoparticles.
These engineered platforms are designed to enhance siRNA stability, improve tumor targeting, facilitate intracellular trafficking,
and promote endosomal escape while minimizing off-target effects and immune activation. Preclinical findings suggest signifi-
cant biological potential; however, additional research is required to address issues concerning biodistribution, safety, scalability,
and regulatory standardization before clinical application. Overall, siRNA-based strategies may play a crucial role in the future
development of precision-oriented therapeutic frameworks in GC research. Importantly, this review emphasizes the integration
of molecular target selection with delivery system design in a GC-specific context. By systematically linking validated siRNA
targets with corresponding nanocarrier strategies, this work provides a more application-oriented and translationally relevant
perspective that is not typically addressed in conventional RNA interference or nanocarrier-focused reviews.
Keywords: siRNA, gastric cancer, gene silencing, nanocarrier delivery, RNA interference.
REVIEWS
C i t a t i o n: Seifollahnezhad G, Erdağ B. Therapeutic role of siRNA in gastric cancer: gene silencing mechanisms and
nanocarrier-based delivery strategies. Exp Oncol. 2026; 48(2): 81-97. https://doi.org/10.15407/exp-oncology.2026.02.081
© PH “Akademperiodyka” of the NAS of Ukraine, 2026. This is an open access article under the CC BY-NC-ND license
(https://creativecommons.org/licenses/by-nc-nd/4.0/)
Gastric cancer (GC) remains a major global health
burden and continues to be associated with unfa-
vorable clinical outcomes, particularly in advanced
or metastatic stages. Despite substantial progress in
molecular profiling and therapeutic stratification,
long-term survival rates remain limited for a sig-
https://doi.org/10.15407/exp-oncology.2026.02.081
mailto:gheysar.seyfolahnezhad@gmail.com
https://doi.org/10.15407/exp-oncology.2026.02.081
https://creativecommons.org/licenses/by-nc-nd/4.0/
82 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
nificant proportion of patients. Tumor heterogene-
ity, dynamic alterations in the tumor microenvi-
ronment, and the frequent emergence of intrinsic
and acquired therapeutic resistance collectively
compromise the efficacy of conventional treatment
modalities [1—3]. Present management strategies
predominantly rely on surgical resection for loca
lized disease and on systemic therapies, including
chemotherapy, targeted agents, and immunothera-
py, for advanced cases. However, the development
of resistance and the limited durability of the re-
sponse remain persistent challenges in clinical
practice [2, 4]. These limitations have stimulated
growing interest in molecularly guided strategies
that selectively modulate resistance-associated and
oncogenic signaling pathways. Among emerging
approaches, RNA interference (RNAi), particularly
small interfering RNA (siRNA), has attracted con-
siderable attention as a sequence-specific gene-si-
lencing technology. In experimental models of GC,
siRNA-based interventions have been investigated
for targeting oncogenic drivers, metastasis-related
regulators, and multidrug resistance–associated
genes [4, 5]. By enabling precise transcript suppres-
sion, siRNA offers a framework for pathway-direc
ted modulation rather than nonspecific cytotoxic
intervention. Nevertheless, the therapeutic applica-
bility of siRNA is critically dependent on the deve
lopment of efficient and biocompatible delivery
systems. The naked siRNA molecules are inherent-
ly unstable in systemic circulation and exhibit li
mited cellular internalization, necessitating protec-
tive and targeted nanocarrier platforms to achieve
functional gene silencing [5]. Consequently, ad-
vances in nanotechnology — including lipid-based
nanoparticles, polymeric systems, peptide-assisted
vectors, biomimetic vesicles, and stimuli-respon-
sive architectures — have become central to the
translational advancement of siRNA-based strate-
gies in oncology. GC is a multifactorial disease
driven by infectious, environmental, genetic, and
lifestyle-related determinants. Helicobacter pylori
infection is still the most well-known cause of
chronic inflammation and molecular changes that
lead to cancer. The diverse molecular landscape of
GC highlights the participation of various signaling
networks, thereby supporting the justification for
gene-targeted regulatory strategies, such as siRNA-
based modulation [6, 7]. In this context, the present
review provides a comprehensive and translation-
ally oriented overview of siRNA-based gene-silen
cing strategies in GC. Particular emphasis is placed
on the molecular targets implicated in tumor pro-
gression and drug resistance, comparative evalua-
tion of emerging nanodelivery platforms, and the
key biological and technological challenges that
must be addressed to facilitate future clinical trans-
lation. To contextualize the clinical limitations that
drive the search for molecularly targeted approa
ches, it is important to consider the current thera-
peutic landscape of GC. Although multimodal
treatment strategies including surgery, chemothe
rapy, targeted therapy, and immunotherapy have
improved disease management in selected patient
populations, their overall impact remains con-
strained by resistance development, systemic toxi
Table 1. Overview of current standard therapeutic strategies
for GC and their major limitations
Treatment modality Representative approaches Major limitations
Surgery Partial or total gastrectomy Limited efficacy in advanced or
metastatic disease
Chemotherapy Fluoropyrimidine- and platinum-based
regimens
Drug resistance and systemic toxicity
Chemoradiotherapy Combined chemotherapy and radiotherapy Benefit dependent on patient selection;
treatment-related toxicity
Targeted therapy Anti-HER2 therapy (e.g., trastuzumab) Restricted to biomarker-positive
patients; acquired resistance
Anti-angiogenic therapy VEGFR2 inhibition (e.g., ramucirumab) Modest survival benefit; resistance
development
Immunotherapy PD-1/PD-L1 inhibitors Limited response rates; lack of robust
predictive biomarkers
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 83
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
city, and limited durability of response. A struc-
tured overview of these standard treatment modal-
ities and their major limitations is presented in
Table 1 [8—13]. Several recent reviews have sum-
marized advances in RNAi-based strategies for GC,
with particular emphasis on drug resistance mech-
anisms and nanoscale delivery platforms [4, 5].
Several recent reviews have addressed RNAi–based
strategies in GC, often focusing either on general
RNAi mechanisms or on the development of nano-
carrier systems as independent topics. While these
studies provide valuable insights, they typically do
not establish a direct relationship between the spe-
cific molecular targets and the selection of appro-
priate delivery platforms within a disease-specific
context. In contrast, the present review adopts a
structured, target-oriented approach that integrates
validated siRNA targets in GC with a comparative
evaluation of nanocarrier systems. By linking mo-
lecular function to delivery strategy, this work aims
to provide a more translationally relevant perspec-
tive, highlighting how target selection and delivery
design can be considered together rather than as
separate components. This integrated framework
may facilitate a more rational design of siRNA-
based strategies in GC research.
This narrative review was based on a compre-
hensive evaluation of the available literature on
siRNA-based strategies in GC. The relevant articles
published between 2006 and 2025 were identified
through searches in major biomedical databases
and academic search engines, including PubMed
and Google Scholar, using combinations of key-
words such as siRNA, RNA interference, GC, and
nanocarrier delivery. Both original experimental
studies (in vitro and in vivo) and review articles
focusing on siRNA targets, delivery systems, and
therapeutic effects in GC were included. Studies
not directly related to GC or siRNA-based ap-
proaches were excluded. The selected literature was
analyzed qualitatively, with particular emphasis on
underlying biological mechanisms, delivery strate-
gies, and their potential translational relevance.
RNAi
RNAi is a post-transcriptional gene regulation
mechanism that enables cells to control gene ex-
pression through small RNA molecules. RNAi-re-
lated processes play a fundamental role in main-
taining cellular homeostasis and regulating biolo
gical responses under physiological and pathological
conditions. In cancer, dysregulation of RNAi-asso-
ciated pathways has been linked to abnormal gene
expression, tumor progression, and altered re-
sponses to therapy. In GC, accumulating evidence
indicates that RNAi-related regulatory mechanisms
contribute to disease development and therapeutic
resistance. These observations have established
RNAi as a relevant biological framework for gene-
silencing approaches and have provided the ratio-
nale for exploring RNAi-based strategies as emer
ging therapeutic tools in GC [14, 15]. Among the
various approaches related to RNAi, siRNA has
emerged as the most thoroughly studied modality,
known for its high sequence specificity and pre-
dictable gene-silencing activity. In contrast to
broader RNAi mechanisms, siRNA enables direct
and targeted suppression of predefined transcripts,
allowing precise modulation of disease-associated
genes. These characteristics have positioned siRNA
as a preferred RNAi-based strategy in cancer re-
search and therapeutic development, including GC.
SiRNAs and their general mechanism are gene
regulators and belong to small RNAs, meaning
they are noncoding, double-stranded RNAs
(dsRNAs). Their complementary nature with
mRNA allows them to silence genes. They have
many biological functions, such as being involved
in transcription and translation. The specific role
of siRNAs in regulating proteins provides them
with potential advantages over many therapies in
treating incurable diseases, particularly cancers.
However, while siRNA medicines are still being
developed with chemical modifications, they lack
an efficient delivery system, limiting their curative
potential [16]. The viral RNA replication interme-
diates and retrotransposon transcripts are exoge-
nous sources that comprise the long dsRNAs from
which short siRNAs are derived [17]. When
dsRNA enters the cytoplasm, Dicer cleaves it into
siRNAs. In humans, Dicer, along with TRBP and
Argonaute (Ago), forms the core of the RNA-in-
duced silencing complex (RISC) assembly path-
way. TRBP stabilizes the Dicer:dsRNA complex
and facilitates the accurate processing of siRNAs.
The siRNA duplex is loaded onto Ago through the
RISC-loading complex (RLC), where the passen-
ger strand is removed, and the guide strand directs
target RNA silencing. This pathway is essential for
84 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
gene regulation and antiviral defense [18]. Addi-
tional proteins, such as PACT and MOV10, en-
hance the gene-silencing function of RISC. Al-
though other proteins may associate with Ago
complexes, they are not essential for loading RISC.
Once the RLC is formed, it loads the siRNA duplex
into Ago2, allowing RISC to target mRNA through
various interaction modes. By receiving the siRNA
duplex and positioning its 5′ ends in the phos-
phate-binding pocket, AGO2 cleaves the passenger
strand, leading to the maturation of active RISC
[19]. The incorporation of ds siRNA, synthesized
by the Dicer enzyme complex (D2/R2), into the
RISC initiates its interaction with Argonaute2
(Ago2). Within the RISC assembly, siRNA under-
goes selective strand dissociation, where the “pas-
senger strand” is cleaved and subsequently dis-
carded. This precise cleavage, facilitated by the en-
donucleolytic activity of Ago2, ensures retention
of only the “guide strand.” The retained guide
strand, now tightly associated with Ago2, enables
the complex to recognize target mRNA. Guided by
this strand, RISC is directed to complementary
mRNA sequences, where Ago2 catalyzes the clea
vage of target mRNA, resulting in gene silencing
through the inhibition of protein synthesis [20].
Key barriers to in vivo siRNA
The therapeutic potential of RNAi has attracted
significant attention, particularly in the context of
cancer therapy. SiRNA, a central component of
RNAi, can downregulate gene expression by pro-
moting the degradation of target mRNA tran-
scripts. This mechanism allows for the selective
silencing of oncogenes and other disease-associa
ted genes. However, numerous barriers related to
in vivo delivery hinder the clinical translation of
siRNA-based therapies, despite their specificity
and versatility [21]. Among the primary challeng-
es is the instability of siRNA under physiological
conditions. In systemic circulation, siRNA mole-
cules are rapidly degraded by serum nucleases,
leading to insufficient bioavailability. Additionally,
their large molecular weight and negatively
charged phosphate backbone inhibit passive diffu-
sion through the hydrophobic lipid bilayer of cell
membranes, resulting in poor cellular uptake [22].
These features necessitate the use of specialized
delivery systems capable of protecting siRNA and
facilitating efficient internalization into the target
cells. Furthermore, siRNA delivery is often com-
plicated by off-target effects, where unintended
genes may be silenced, leading to unpredictable
biological responses. Another significant concern
is immunogenicity, as dsRNA structures can sti
mulate innate immune responses, potentially trig-
gering inflammation or systemic toxicity [21].
Therefore, overcoming these barriers is critical for
the development of safe and effective siRNA-based
therapeutics. In response to these challenges, re-
cent efforts have focused on the design of multi-
functional nanocarrier systems. One study intro-
duced nucleic acid-based nanogels engineered to
provide both protective and functional roles du
ring siRNA transport. These nanogels were de-
signed to shield siRNA from enzymatic degrada-
tion and immune detection (“defensive”), while
simultaneously enhancing tumor penetration and
endosomal escape (“offensive”). In vivo studies on
such nanogels have reported improvements in
siRNA stability and intracellular delivery efficien-
cy, indicating their potential as delivery vehicles in
RNAi research [23]. This approach highlights the
potential of smart delivery systems in addressing
multifaceted obstacles associated with in vivo
siRNA therapy. As shown in the Figure, multiple
siRNA delivery systems—including lipid-based,
peptide-based, and biomimetic carriers—have
been developed to overcome in vivo barriers and
improve therapeutic outcomes in GC models.
Lipid-based nanocarriers
Lipid-based nanocarriers have been investigated as
effective platforms for siRNA delivery in GC mod-
els. In one study, lipid nanoparticles (LNPs) were
engineered to deliver siRNA targeting TMPRSS4, a
gene associated with tumor progression and inva-
sion in GC. The formulated LNPs exhibited effi-
cient cellular uptake in the NUGC-3 GC cells and
demonstrated intracellular localization following
endocytosis, with subsequent release of siRNA into
the cytoplasm. Gene silencing analysis confirmed
a marked reduction in the TMPRSS4 protein ex-
pression, indicating the effective delivery and func-
tional activity of the siRNA cargo [24]. In vivo eval-
uation using a GC xenograft mouse model showed
enhanced accumulation of LNP-delivered siRNA
within tumor tissue compared to the naked siRNA.
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 85
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
Notably, the combination of siRNA-loaded LNPs
with fluorouracil resulted in a significant suppres-
sion of tumor growth compared to chemotherapy
alone [24]. Similarly, another study developed
AS1411-functionalized LNPs for targeted delivery
of Bmi-1 siRNA in GC. These nanoparticles dem-
onstrated efficient gene silencing, with Bmi-1 ex-
pression reduced by approximately 63% in the
MGC-803 GC cells following treatment, which was
associated with decreased tumor cell proliferation
and increased apoptosis in vitro [25]. In vivo ex-
periments further confirmed that these LNPs sig-
nificantly inhibited tumor growth and promoted
apoptosis in tumor tissues while maintaining favo
rable biosafety profiles [25]. Collectively, these fin
dings highlight the capability of lipid-based nano-
carriers to facilitate effective siRNA delivery and
induce antitumor effects in preclinical GC models.
Taken together, lipid-based nanocarriers appear to
represent one of the most advanced and extensive-
ly investigated platforms for siRNA delivery in GC,
particularly due to their ability to achieve efficient
encapsulation, promote intracellular release, and
demonstrate measurable in vivo tumor accumula-
tion. However, despite these encouraging preclini-
cal findings, several limitations remain. In particu-
lar, long-term biosafety, large-scale manufacturing
reproducibility, and the stability of these systems
under physiologically relevant conditions have not
yet been fully clarified. Therefore, further studies
are required to determine whether the delivery ef-
ficiency observed in experimental models can be
consistently translated into clinically relevant the
rapeutic outcomes.
Peptide-based siRNA
delivery systems
Peptide-assisted delivery has been investigated as
an approach to enhance the intracellular transport
of siRNA in GC cells. In this context, a low-mole
cular-weight protamine (LMWP), recognized as a
cell-penetrating peptide, was used to modify PEG-
SS-PEI-based nanoparticles for the delivery of
BRD4-targeting siRNA. The incorporation of
LMWP improved the cellular uptake of siRNA
nanoparticles, as indicated by increased fluores-
cence intensity in the HGC-27 and SGC-7901 cells
compared to non-modified systems. Intracellular
localization studies showed that the nanoparticles
were initially associated with lysosomes following
uptake, while LMWP modification facilitated the
escape of siRNA into the cytoplasm over time. Ad-
ditionally, the nanocarrier system exhibited redox-
responsive behavior, with enhanced siRNA release
in glutathione-containing environments, sugges
ting a responsive release profile under intracellular
conditions. Functional analyses demonstrated that
delivery of BRD4 siRNA using LMWP-modified
nanoparticles was associated with reduced proli
feration, migration, and invasion of GC cells. These
effects were accompanied by decreased BRD4 ex-
pression and modulation of downstream signaling
pathways, including PI3K/AKT and c-MYC. Over-
all, these findings indicate that peptide-modified
nanocarriers can improve the delivery efficiency
and intracellular release of siRNA in GC cells, sup-
porting their role in the development of siRNA de-
livery systems [26]. In contrast to carrier systems
that primarily enhance systemic stability or tumor
accumulation, peptide-assisted platforms appear to
exert their main advantage at the intracellular level,
particularly by facilitating membrane translocation
and promoting endosomal escape. This feature is
especially relevant in the context of siRNA delivery,
where inefficient cytoplasmic release remains a key
limiting factor. Nevertheless, despite these func-
tional advantages, the broader applicability of pep-
tide-based systems remains uncertain. Their sus-
ceptibility to enzymatic degradation, relatively
short circulation time, and potential variability in
delivery efficiency across different tumor microen-
vironments may limit their performance beyond
controlled experimental settings. Consequently,
further investigation is required to determine
whether these systems can achieve consistent in
vivo stability and delivery efficiency suitable for
translational application.
Polymeric and polyelectrolyte-
based systems
Polymeric and polyelectrolyte-based delivery sys-
tems have been widely investigated as platforms for
siRNA delivery due to their structural versatility
and their ability to form stable complexes through
electrostatic interactions. In GC, cationic polymers
such as polyethyleneimine (PEI) have been exten-
sively employed to condense negatively charged
siRNA into nanoscale complexes, facilitating cel-
86 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
lular uptake and intracellular delivery [27, 28]. The
efficiency of these complexes is strongly influenced
by the nitrogen-to-phosphate (N/P) ratio, which
plays a critical role in determining stability, trans-
fection efficiency, and cytotoxicity [27]. Surface
modification of polymeric carriers with polyethy
lene glycol (PEG) has been shown to improve their
performance in biological environments. PEGylat-
ed systems, such as PEG–g–PEI, exhibit enhanced
stability, reduced cytotoxicity, and improved bio-
compatibility while maintaining efficient siRNA
condensation and delivery capabilities. These mo
difications also contribute to better dispersion and
interaction with GC cells, supporting more effec-
tive intracellular transport of siRNA [28]. In addi-
tion to nanoparticle-based systems, polymer–
siRNA complexes have also been incorporated into
advanced delivery platforms such as hydrogels to
achieve sustained release profiles. For example,
PEI-based siRNA complexes embedded in in situ-
forming hydrogels have demonstrated prolonged
retention and enhanced delivery efficiency in GC
models while maintaining gene silencing activity
over extended periods [29]. Despite these advan-
tages, polymer-based siRNA delivery systems still
face several challenges, including cytotoxicity as-
sociated with cationic polymers and the need for
further optimization of delivery efficiency and
specificity, particularly in terms of targeting spe-
cific tissues and minimizing off-target effects. On-
going studies, therefore, focus on improving poly-
mer design and developing safer and more efficient
delivery platforms [27—29]. From a formulation
perspective, polymeric and polyelectrolyte-based
systems offer a high degree of tunability in siRNA
delivery, allowing precise control over particle size,
surface charge, and release kinetics. This flexibility
enables the design of delivery platforms that can be
adapted to specific biological requirements in GC
models. However, a fundamental challenge in these
systems lies in balancing transfection efficiency
with biocompatibility. While higher cationic charge
densities may improve siRNA condensation and
cellular uptake, they are also associated with in-
creased cytotoxicity and potential adverse interac-
tions with biological components. Moreover, the
performance of these systems can be influenced by
variations in formulation parameters and biological
conditions, which may affect their reproducibility
and consistency. Therefore, further optimization is
required to achieve a balance among delivery effi-
ciency, safety, and scalable production for potential
translational applications.
Chitosan-based nanoparticles
Chitosan-based nanoparticles have been extensive-
ly investigated as non-viral carriers for siRNA de-
livery due to their ability to form electrostatic com-
plexes with negatively charged nucleic acids. In GC
models, chitosan has been used to encapsulate
siRNA into nanoscale particles, facilitating cellular
uptake and intracellular delivery. For instance, chi-
tosan-mediated delivery of BRAF siRNA has been
shown to effectively reduce target gene expression
in GC cells, demonstrating the capability of these
systems to support RNAi processes [30]. Structural
modification of chitosan has also been explored to
improve delivery performance under gastrointesti-
nal conditions. The modified chitosan derivatives,
including imidazole-grafted and trimethylated
forms, have been utilized to enhance nanoparticle
stability and enable penetration through the gastric
mucus barrier, allowing more efficient interaction
with gastric epithelial and carcinoma cells. These
systems, relying on spontaneous electrostatic inte
ractions to form siRNA-loaded nanoparticles, have
demonstrated the ability to modulate gene expres-
sion in relevant gastric cell models [31]. In addi-
tion, advanced chitosan-based nanocarriers have
been developed for co-delivery applications. Cho-
lesterol-modified chitosan micelles have been de-
signed to simultaneously incorporate siRNA and
hydrophobic drugs, forming stable nanostructures
with suitable physicochemical properties, such as
controlled particle size and surface charge. These
systems have shown improved cellular uptake and
enhanced intracellular delivery behavior in GC cell
lines, supporting their use as multifunctional deliv-
ery platforms [32]. Despite these developments,
chitosan-based systems still require further optimi-
zation in terms of stability, delivery efficiency, and
reproducibility. Current approaches therefore focus
on structural modification and formulation strate-
gies to improve performance in biological environ-
ments [30—32]. As biocompatible and mucoadhe-
sive polymers, chitosan-based systems are particu-
larly relevant for GC applications, where interaction
with the gastrointestinal environment plays a criti-
cal role in delivery performance. Their ability to
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 87
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
penetrate the gastric mucus layer and form stable
electrostatic complexes with siRNA provides a con-
text-specific advantage over some synthetic carri-
ers. However, despite these favorable properties,
variability in physicochemical characteristics—
such as degree of deacetylation, molecular weight,
and formulation conditions—can significantly in-
fluence delivery efficiency and reproducibility. In
addition, maintaining nanoparticle stability under
dynamic gastrointestinal conditions remains a
challenge. Therefore, further standardization of
formulation parameters and improved control over
physicochemical properties are required to ensure
consistent performance and facilitate potential
translational development.
Exosome-based
and biomimetic nanocarriers
Exosome-based nanocarriers have emerged as bio-
logically derived delivery systems for nucleic acids,
including siRNA, due to their inherent compatibil-
ity with cellular processes and their ability to medi-
ate intercellular communication. In GC models,
exosomes have been utilized as carriers to transfer
siRNA into tumor cells, facilitating intracellular de-
livery through natural uptake mechanisms. For ex-
ample, exosome-mediated delivery of c-MET siRNA
has been shown to enable efficient internalization
into GC cells and modulation of target gene expres-
sion, highlighting the suitability of these vesicles as
gene delivery platforms [33]. Mesenchymal stem
cell derived exosomes have also been explored as
nanocarriers in GC systems due to their affinity
for tumor microenvironments and their capacity
for drug and nucleic acid loading. These exosomes
can encapsulate therapeutic cargos such as siRNA
and chemotherapeutic agents, and their nanoscale
size allows effective interaction with GC cells. The
experimental observations indicate that exosome-
based formulations enhance cellular uptake and
intracellular accumulation of the delivered mole-
cules compared to free agents. Additionally, exo-
somes exhibit favorable biological properties, in-
cluding low immunogenicity and natural mem-
brane composition, which support their function
as delivery vehicles in complex biological environ-
ments [34]. Their ability to transport molecular
cargo across cellular barriers and deliver it direct-
ly into recipient cells further contributes to their
application in siRNA delivery strategies. Neverthe-
less, challenges remain in controlling loading effi-
ciency, standardizing exosome isolation, and en-
suring reproducibility of these systems, which are
critical considerations for further development
[33, 34]. Biologically derived carriers such as exo-
somes offer a distinct conceptual advantage over
synthetic nanocarriers, as they are inherently
adapted for intercellular communication and mo-
lecular transport. This intrinsic compatibility may
enhance delivery efficiency and reduce immune-
related limitations in GC models. However, unlike
engineered nanoparticle systems, exosome-based
platforms are more difficult to standardize and
control, particularly in terms of cargo loading ef-
ficiency, isolation methods, and batch-to-batch
consistency. In addition, large-scale production
and reproducible manufacturing remain signifi-
cant challenges that limit their current translation-
al applicability. Therefore, while exosome-based
systems demonstrate promising biological func-
tionality, further methodological optimization and
standardization are required before they can be re-
liably integrated into therapeutic strategies.
Stimuli-responsive and
theranostic delivery platforms
Stimuli-responsive delivery platforms have been
developed to enhance the controlled release and
intracellular availability of siRNA in cancer sys-
tems by exploiting specific features of the tumor
microenvironment. In GC models, redox-respon-
sive nanoparticles have been designed to release
siRNA under elevated intracellular reducing condi-
tions, thereby facilitating efficient cytoplasmic de-
livery and improving gene-silencing performance
[26]. These systems rely on the environmentally
sensitive linkages that remain stable under physio
logical conditions but undergo structural changes
within tumor cells, enabling selective siRNA re-
lease. In addition to stimuli-responsive strategies,
theranostic delivery platforms integrate both diag-
nostic and delivery functions within a single nano-
system. For instance, superparamagnetic iron oxi
de nanoparticle-based systems have been utilized
as magnetic resonance imaging (MRI)-visible car-
riers for siRNA delivery in GC models [35]. These
nanocarriers enable simultaneous tracking of
nanoparticle distribution and cellular uptake while
88 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
mediating intracellular transport of siRNA. The in-
corporation of imaging capability provides real-
time insight into biodistribution and delivery ef-
ficiency without altering the fundamental delivery
function of the system. Overall, the combination of
stimuli-responsive release mechanisms and the
ranostic functionalities represents an advanced ap-
proach in siRNA delivery design, allowing im-
proved control over intracellular release and ena
bling monitoring of delivery processes in GC
models [26, 35]. From a design perspective, stim-
uli-responsive and theranostic platforms introduce
an additional level of functional sophistication by
enabling environment-specific siRNA release and
real-time monitoring of delivery processes. This
dual capability may provide a strategic advantage
in addressing key barriers such as inefficient intra-
cellular release and unpredictable biodistribution.
However, the increased structural and functional
complexity of these systems may also introduce
challenges related to formulation reproducibility,
scalability, and comprehensive safety evaluation. In
particular, it remains unclear whether the added
multifunctionality consistently translates into su-
perior therapeutic outcomes compared to simpler
delivery systems. Therefore, further studies are re-
quired to determine the practical benefit–risk ba
lance of these advanced platforms in the context of
translational application.
Layer-by-layer nanocarriers
for siRNA delivery
Layer-by-layer (LbL) assembled nanoparticles have
been investigated as a strategy for enhancing the
delivery efficiency of siRNA in GC models. In one
study, LbL-based siRNA nanoparticles were devel-
oped to target glioma-associated oncogene homo-
log 1 (GLI1) in gastric cancer stem cells (CSCs).
These nanoparticles were constructed using a LbL
assembly approach and further functionalized with
hyaluronic acid to enable CD44-mediated target-
ing. The developed nanoparticles demonstrated ef-
ficient cellular uptake and targeting capability in
gastric CSCs. Functional analyses showed that
GLI1 siRNA delivery via these LbL nanoparticles
resulted in a significant reduction in the GLI1 pro-
tein expression. In addition, the system inhibited
key cellular behaviors associated with malignancy,
including tumor sphere formation, migration, and
invasion of gastric CSCs. Furthermore, in vivo
evaluation indicated that the nanoparticles accu-
mulated in tumor tissues and suppressed tumor re-
currence. Mechanistically, these effects were associ-
ated with the inhibition of the Hedgehog signaling
pathway, which plays a critical role in the mainte-
nance and progression of gastric CSCs. Overall,
this study demonstrated that LbL-assembled siR-
NA nanoparticles can serve as an effective platform
for targeted gene silencing in GC models, particu-
larly through CD44-mediated delivery and path-
way-specific inhibition [36]. As illustrated in the
Figure, several nanocarrier platforms have been ex-
plored for the delivery of siRNA in cancer therapy,
including lipid-based nanoparticles, polymeric
nanoparticles, peptide-based carriers, exosomes,
and other biomimetic nanovesicles, each designed
to enhance siRNA stability, cellular uptake, and tu-
mor-targeted delivery. Compared with other nano-
carrier systems, LbL-assembled nanoparticles pro-
vide a highly modular and customizable platform,
allowing precise control over surface composition,
targeting ligands, and release behavior. This struc-
tural flexibility enables the integration of multiple
functional layers that can be tailored to address
specific biological barriers in GC models, particu-
larly in the context of cancer stem cell targeting.
However, despite these advantages, the current ev-
idence remains largely based on platform-specific
designs, and the reproducibility of multilayer as-
sembly under scalable manufacturing conditions
has not yet been fully established. Therefore, fur-
ther studies are required to determine whether
these systems can be reliably standardized and ap-
plied across broader GC contexts.
Comparison of different
delivery platforms
From a broader comparative perspective, lipid-
based nanoparticles appear to be among the most
advanced and clinically translatable platforms due
to their high encapsulation efficiency and demon-
strated in vivo performance. In contrast, polymeric
and chitosan-based systems offer greater structural
flexibility and tunability but may be limited by cy-
totoxicity and formulation variability. Peptide-
based carriers primarily enhance intracellular de-
livery and endosomal escape; however, their in vivo
stability remains a concern. Exosome-derived sys-
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 89
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
tems provide superior biocompatibility and natural
targeting capabilities, although challenges related
to standardization and large-scale production re-
strict their translational potential. Stimuli-respon-
sive and theranostic platforms introduce addition-
al functional advantages, such as controlled release
and imaging capability, but their increased struc-
tural complexity may affect reproducibility and
clinical applicability. Overall, no single delivery sys-
tem is universally optimal, and the selection of an
Table 2. Nanocarrier-based siRNA delivery systems in GC:
target genes and preclinical functional outcomes
Delivery system Target gene Strategy Experimental model Main findings References
Exosome mimetic
nanocarriers
NPR1 siRNA-mediated
silencing via en-
gineered exosome
mimetics
In vitro and in vivo
(GC metastasis
model)
NPR1 silencing
reduced lipid droplet
lipolysis, decreased
mitochondrial oxida-
tive phosphorylation,
and inhibited gastric
cancer metastasis
[37]
Chitosan
nanoparticles
(CH-NP)
RNU11 siRNA delivery
using chitosan-based
nanoparticles
GCcell lines (AGS,
HGC27) and
xenograft mouse
model
Silencing of RNU11
inhibited GC cell pro-
liferation, migration,
and induced apoptosis
[38]
Layer-by-layer (LbL)
nanoparticles
GLI1 siRNA delivery
using LbL assembled
nanoparticles
Gastric CSCs (in
vitro) and in vivo
tumor model
Silencing of GLI1
reduced tumor sphere
formation, migration,
and invasion of gastric
CSCs
[36]
PEG-SS-PEI
nanoparticles
(LMWP-modified)
BRD4 siRNA delivery using
redox-responsive
polymeric nanopar-
ticles
In vitro (GC cell
lines)
BRD4 silencing
inhibited prolifera-
tion, migration, and
invasion via suppres-
sion of PI3K/AKT
and c-MYC signaling
pathways
[26]
Lipid nanoparticles
(LNPs)
TMPRSS4 Anti-TMPRSS4
siRNA delivery us-
ing engineered lipid
nanoparticles
In vitro (NUGC-3
cells) and in vivo
(xenograft mouse
model)
Enhanced tumor accu-
mulation; significant
tumor growth reduc-
tion; improved effect
in combination with
5-FU
[24]
Folic acid–func-
tionalized poly
ethyleneimine
superparamagnetic
iron oxide nanopar-
ticles (FA-PEG-SS-
PEI-SPION)
PD-L1 siRNA delivery using
folic acid-function-
alized PEI-based
magnetic nanopar-
ticles with disulfide
linkage
GC cell line
(SGC‑7901)
Efficient cellular
uptake and PD-L1
gene silencing; the
nanoparticles also
showed MRI-related
imaging potential
[35]
scFv(CD44v6)-PEG-
g-PEI functionalized
superparamagnetic
iron oxide nanopar-
ticles (PEG-g-PEI-
SPION)
CD44v6 Antibody-directed
siRNA delivery using
PEG-g-PEI func-
tionalized magnetic
nanoparticles
In vitro and in vivo Effective siRNA trans-
fer, cellular uptake,
and distribution con-
firmed by fluorescence
imaging and immuno-
fluorescence staining;
targeting effect verified
by MRI and histology
[39]
90 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
appropriate platform should be guided by the bio-
logical characteristics of the target and the specific
therapeutic context in GC. To better compare the
characteristics of different nanocarrier platforms
used for siRNA delivery, Table 2 summarizes rep-
resentative delivery systems investigated in GC re-
search, together with their target genes, experi-
mental models, and reported preclinical function-
al outcomes.
The nanocarrier platforms summarized above
highlight the critical role of delivery system design
in improving siRNA stability, cellular uptake, and
intracellular release in GC models. Despite these
advances, most studies still operate in preclinical
settings, highlighting the necessity for further vali-
dation and clinical translation. While the optimiza-
tion of the nanocarrier systems is essential for ef-
ficient siRNA delivery, the observed biological ef-
fects of these approaches largely depend on the
selection of biologically relevant molecular targets.
In GC research, siRNA-based strategies have been
widely used to investigate genes and signaling path-
ways involved in tumor progression and cellular
processes. In this context, Table 3 summarizes the
representative molecular targets and the functional
outcomes observed following siRNA-mediated
gene silencing in preclinical models.
Table 3 provides a structured overview of repre-
sentative molecular targets examined in siRNA-
based experimental studies of GC, integrating their
biological roles with the phenotypic outcomes ob-
served after gene silencing. The compiled evidence
indicates that the investigated targets are primarily
involved in regulatory pathways governing tumor
cell proliferation, survival, apoptosis, invasion, me-
tastasis, angiogenesis, and metabolic adaptation.
Despite the heterogeneity of these targets, siRNA-
mediated suppression frequently yields comparable
biological effects, including reduced cell prolifera-
tion, decreased migration and invasion, and in-
Schematic categorization of siRNA delivery systems relevant to GC research. The figure outlines major nanocarrier stra
tegies distinguished by their physicochemical properties and functional mechanisms. Lipid-based nanoparticles enable
efficient siRNA encapsulation and promote endosomal escape. Exosome-derived carriers offer intrinsic biocompatibility
and cellular targeting capabilities. Chitosan-based systems facilitate electrostatic complexation and exhibit mucoadhe-
sive behavior. Polyelectrolyte micelles provide tunable release kinetics and improve colloidal stability. Peptide-based vec-
tors enhance membrane translocation and intracellular uptake. Stimuli-responsive platforms allow condition-specific
release based on environmental triggers. Biomimetic nanocarriers incorporate cell-derived membranes to support im-
mune evasion and prolonged circulation
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 91
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
creased apoptotic activity. This pattern suggests
that modulation of distinct molecular pathways
may yield overlapping phenotypic responses, re-
flecting the interconnected nature of GC signaling
networks. Overall, the findings summarized in Ta-
ble 3 highlight consistent functional outcomes ob-
served in preclinical models following siRNA-me-
diated gene silencing. These observations should
be interpreted in light of the multiple experimental
and biological limitations, as further discussed in
the following section.
Promising siRNA targets in GC
Among the targets summarized in Table 3, several
appear particularly promising because their silen
cing was associated with strong antitumor effects
and, in some cases, validation in both in vitro and
in vivo models. PKM2, Notch1, ABL (lncRNA),
STAT3, VEGF, and Survivin (BIRC5) showed high
translational relevance in line with evidence from
in vivo or combined in vitro/in vivo models. These
targets are involved in major functional processes
of GC progression, including metabolic adaptation,
oncogenic signaling, apoptosis resistance, angiogen-
esis, drug resistance, and tumor growth. For exam-
ple, siRNA-mediated knockdown of PKM2 reduced
cell proliferation and tumor growth under hypoxic
conditions [43], whereas Notch1 silencing en-
hanced doxorubicin sensitivity, induced apoptosis,
and inhibited tumor growth [46]. Similarly, STAT3
silencing suppressed tumor growth, reduced prolif-
eration, and promoted apoptosis [50], while VEGF
knockdown reduced tumor volume and weight in
vivo [51]. Survivin silencing also suppressed tumor
growth and induced apoptosis in xenograft models
[52]. Other high-value targets, including CD44v6,
Bcl-XL (BCL2L1), EZH2, and DcR3, also demon-
strated biologically relevant effects following siRNA-
mediated inhibition. CD44v6 is notable because of
its association with CSC features, tumor progres-
sion, and metastasis, although the reported evi-
dence primarily emphasized delivery efficiency
rather than broader functional validation [27].
Bcl‑XL, EZH2, and DcR3 are mainly linked to tu-
mor cell survival, chemoresistance, and apoptosis
regulation. Their silencing enhanced cytotoxicity,
inhibited proliferation, reversed cisplatin resistance,
or increased sensitivity to 5-fluorouracil [44, 47,
48]. These findings suggest that apoptosis- and re-
sistance-associated targets may be especially rele-
vant for combination strategies in GC. In contrast,
the targets with moderate translational value, in-
cluding NEDD9, S100A4, ZNRD1, Rac1, ARH-
GAP9, and ZNF139, also produced meaningful
phenotypic effects such as reduced migration, inva-
sion, proliferation, EMT-related changes, or en-
hanced apoptosis [40—42, 45, 53, 54]. However,
their current evidence is largely restricted to in vitro
models, specific cell lines, or limited experimental
contexts. Therefore, while these targets remain bio-
logically important, further in vivo validation and
more comprehensive functional assessment are re-
quired before their translational potential can be
considered comparable to the high-value targets
summarized in Table 3.
Challenges and future directions
of siRNA therapeutics in GC
Despite the growing interest in siRNA-based strat-
egies for GC, several critical challenges continue to
limit their clinical translation. One of the primary
barriers is the inherent instability of naked siRNA
in biological environments, where they are highly
susceptible to enzymatic degradation and rapid
clearance from circulation, resulting in limited bio-
availability and reduced therapeutic efficacy [5,
22]. In addition, the efficient delivery of siRNA to
tumor tissues remains a major obstacle. The large
molecular size and negative charge of siRNA hin-
der its ability to cross cellular membranes, while
biological barriers such as dense extracellular ma-
trix and abnormal tumor vasculature restrict
nanoparticle penetration and distribution within
gastric tumors [4, 5, 23]. In the context of GC, the
additional disease-specific factors further compli-
cate delivery efficiency. The gastric microenviron-
ment is characterized by acidic conditions and a
protective mucus layer, both of which can influence
nanoparticle stability and reduce delivery perfor-
mance, particularly for orally or locally adminis-
tered systems [22]. Moreover, tumor heterogeneity
in GC — encompassing variations in gene expres-
sion, stromal composition, and cellular subpopula-
tions — can significantly affect target accessibility
and therapeutic response [4, 23]. Even after suc-
cessful cellular uptake, the intracellular barriers re-
main a key limitation. The endosomal entrapment
reduces the cytoplasmic availability of siRNA,
92 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
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ISSN 1812-9269. Experimental Oncology 48 (2). 2026 93
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
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94 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
thereby limiting gene-silencing efficiency. In addi-
tion, off-target effects and unintended immune ac-
tivation remain important safety concerns, as
siRNA molecules may interact with non-specific
transcripts or activate innate immune pathways [5,
22]. Another major challenge is the complexity of
oncogenic signaling in GC, where multiple path-
ways often operate simultaneously. Consequently,
targeting a single gene may be insufficient to
achieve sustained therapeutic effects, highlighting
the need for combinational or multitarget strategies
[4, 54]. Finally, most of the available evidence for
siRNA-based therapies in GC is derived from pre-
clinical studies, with limited clinical validation. The
challenges related to large-scale manufacturing,
formulation reproducibility, and regulatory stan-
dardization further hinder clinical translation. To
address these challenges, future research should fo-
cus on the rational design of nanocarrier systems
that integrate stability, targeting specificity, and ef-
ficient intracellular release. In particular, multi-
functional delivery platforms capable of overcom-
ing multiple biological barriers simultaneously may
improve therapeutic outcomes [5, 23]. Combina-
tion strategies, including co-delivery of siRNA with
chemotherapeutic agents, have shown potential in
enhancing chemosensitivity and overcoming drug
resistance in the GC models [4, 23]. In addition, ad-
vances in the chemical modification of siRNA mol-
ecules may improve stability, reduce immunogenic-
ity, and enhance target specificity. Personalized ap-
proaches based on molecular profiling of GC may
further enable the selection of optimal siRNA targets
and delivery strategies [4]. Importantly, future prog-
ress will depend on the development of scalable
manufacturing processes, standardized delivery sys-
tems, and well-designed clinical studies to evaluate
safety and efficacy. Addressing these factors will be
essential for translating siRNA-based strategies
from experimental models into clinically applicable
therapies for GC [5, 23].
The siRNA-based strategies represent a rapidly
evolving and precision-oriented approach in GC
research, particularly at the preclinical stage. Ex-
perimental studies have demonstrated that siRNA-
mediated modulation of molecular targets can in-
fluence key malignant phenotypes, such as prolif-
eration, invasion, apoptosis, and chemosensitivity.
These findings underscore the potential of tran-
script-level intervention in addressing gastric tu-
mor heterogeneity and resistance-associated me
chanisms. Concurrently, advances in nanotechno
logy have enabled the development of diverse
delivery platforms, including lipid-based nanopar-
ticles, polymeric systems, chitosan-derived carri-
ers, peptide-assisted vectors, biomimetic vesicles,
and stimuli-responsive architectures. These sys-
tems are designed to enhance siRNA stability,
improve tumor targeting, and facilitate intracel-
lular release. However, despite these technologi-
cal developments, significant challenges remain,
particularly in vivo biodistribution, long-term
safety, immune activation, manufacturing repro-
ducibility, and regulatory standardization. Im-
portantly, current evidence suggests that the ef-
fectiveness of siRNA-based approaches in GC is
not solely dependent on target selection or deliv-
ery system design alone, but rather on the inte-
gration of both components. The coordinated
consideration of molecular targets and delivery
strategies may therefore represent a critical factor
in improving translational outcomes. Overall,
while siRNA-based modulation demonstrates
considerable biological promise in GC models,
further optimization of delivery systems, valida-
tion in clinically relevant settings, and standar
dization of translational frameworks are required
before therapeutic applicability can be fully rea
lized. The continued interdisciplinary collabora-
tion across RNA biology, materials science, and
oncology will be essential to advance the clinical
potential of these strategies.
REFERENCES
1. Mazurek M, Szewc M, Sitarz MZ, et al. Gastric cancer: An up-to-date review with new insights into early-onset gas-
tric cancer. Cancers (Basel). 2024;16(18):3163. https://doi.org/10.3390/cancers16183163
2. Alsina M, Arrazubi V, Diez M, et al. Current developments in gastric cancer: from molecular profiling to treatment
strategy. Nat Rev Gastroenterol Hepatol. 2023;20(3):155-170. https://doi.org/10.1038/s41575-022-00703-w
3. Panahizadeh R, Panahi P, Asghariazar V, et al. A literature review of recent advances in gastric cancer treatment:
Exploring the cross-talk between targeted therapies. Cancer Cell Int. 2025;25:23. https://doi.org/10.1186/s12935-
025-03655-8
4. Khaleel AQ, Alshahrani MY, Rizaev JA, et al. siRNA-based strategies to combat drug resistance in gastric cancer. Med
Oncol. 2024;41(11):293. https://doi.org/10.1007/s12032-024-02528-w
https://doi.org/10.3390/cancers16183163
https://doi.org/10.1038/s41575-022-00703-w
https://doi.org/10.1186/s12935-025-03655-8
https://doi.org/10.1186/s12935-025-03655-8
https://doi.org/10.1007/s12032-024-02528-w
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 95
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
5. Hashemi M, Aparviz R, Beickzade M, et al. Advances in RNAi therapies for gastric cancer: Targeting drug resistance
and nanoscale delivery. Biomed Pharmacother. 2023;169:115927. https://doi.org/10.1016/j.biopha.2023.115927
6. Burz C, Pop V, Silaghi C, et al. Helicobacter pylori infection in patients with gastric cancer: a 2024 update. Cancers
(Basel). 2024;16(11):1958. https://doi.org/10.3390/cancers16111958
7. Pu K, Feng Y, Tang Q, et al. Review of dietary patterns and gastric cancer risk: Epidemiology and biological evi-
dence. Front Oncol. 2024;14:1333623. https://doi.org/10.3389/fonc.2024.1333623
8. Shitara K, Fleitas T, Kawakami H, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis,
treatment and follow-up of patients with gastric cancer. ESMO Open. 2024;9(2):102226. https://doi.org/10.1016/j.
esmoop.2023.102226
9. Eom SS, Ryu KW, Han HS, et al. A comprehensive and comparative review of global gastric cancer treatment guide-
lines: 2024 update. J Gastric Cancer. 2025;25(1):153-176. https://doi.org/10.5230/jgc.2025.25.e10
10. Khan A, Rath S, Fatima M, et al. Efficacy and safety of chemoradiotherapy versus chemotherapy for resectable gastric cancer:
a systematic review and meta-analysis. Ann Med Surg. 2025;87:5973-5989. https://doi.org/10.1097/MS9.0000000000003608
11. He L, Liu B, Wang Z, et al. Evolving landscape of HER2-targeted therapies for gastric cancer patients. Curr Treat
Options Oncol. 2025;26(4):260-277. https://doi.org/10.1007/s11864-025-01300-0
12. Wu Z, Ni J, Xu Q. Clinical advances and challenges of anti-angiogenic targeted therapy in gastric cancer. Front
Oncol. 2025;15:1654300. https://doi.org/10.3389/fonc.2025.1654300
13. Zhang G, Lin G, Zhou Z, et al. Bibliometric analysis of anti-angiogenic therapy in gastric cancer: Research hotspots,
trends, and emerging frontiers. Int J Clin Pharm. 2026;48(1):274-283. https://doi.org/10.1007/s11096-025-02055-2
14. Lupan I, Bintintan V, Deleanu D, et al. Epigenetic regulation of DNA methylation and RNA interference in gastric
cancer: a 2024 update. Biomedicines. 2024;12(9):2001. https://doi.org/10.3390/biomedicines12092001
15. Singh J, Saeedan AS, Kaithwas G, et al. Small interfering RNA: From designing to therapeutic in cancer. J Genet Eng
Biotechnol. 2025;23(2):100484. https://doi.org/10.1016/j.jgeb.2025.100484
16. Dana H, Chalbatani GM, Mahmoodzadeh H, et al. Molecular mechanisms and biological functions of siRNA. Int
J Biomed Sci. 2017;13(2):48-57.
17. Zhou R, Rana TM. RNA-based mechanisms regulating host-virus interactions. Immunol Rev. 2013;253(1):97-111.
https://doi.org/10.1111/imr.12046
18. Paturi S, Deshmukh MV. A glimpse of “Dicer biology” through the structural and functional perspective. Front Mol
Biosci. 2021;8:643657. https://doi.org/10.3389/fmolb.2021.643657
19. Li X, Wang X, Cheng Z, et al. AGO2 and its partners: a silencing complex, a chromatin modulator, and new fea-
tures. Crit Rev Biochem Mol Biol. 2020;55(1):33-53. https://doi.org/10.1080/10409238.2020.1738331
20. Wilson RC, Doudna JA. Molecular mechanisms of RNA interference. Annu Rev Biophys. 2013;42:217-239. https://
doi.org/10.1146/annurev-biophys-083012-130404
21. Singh A, Trivedi P, Jain NK. Advances in siRNA delivery in cancer therapy. Artif Cells Nanomed Biotechnol.
2018;46(2):274-283. https://doi.org/10.1080/21691401.2017.1307210
22. Losurdo P, de Manzini N, Palmisano S, et al. Potential application of small interfering RNA in gastrointestinal tu-
mors. Pharmaceuticals (Basel). 2022;15(10):1295. https://doi.org/10.3390/ph15101295
23. Wang S, Li J, Zhang Z, et al. Advances in nanomedicine and delivery systems for gastric cancer research. Front
Bioeng Biotechnol. 2025;13:1565999. https://doi.org/10.3389/fbioe.2025.1565999
24. Tazawa H, Ishida Y, Suzuki T, et al. Delivery of lipid nanoparticles containing small interfering RNA targeting
transmembrane serine protease 4 in a human gastric cancer model using nude mice. Sci Rep. 2025;15(1):45053.
https://doi.org/10.1038/s41598-025-32407-x
25. Yan H, Shen H, Situ J, et al. Preparation of Bmi-1-siRNA lipid nanoparticles and effects in gastric cancer. Nano
Biomed Eng. 2024;16(3):135-143. https://doi.org/10.26599/NBE.2024.9290086
26. Zhang M, An Z, Jiang Y, et al. Self-assembled redox-responsive BRD4 siRNA nanoparticles: formulation and its in vit
ro delivery in gastric cancer cells. J Chemother. 2025;37(1):45-59. https://doi.org/10.1080/1120009X.2024.2308980
27. Wu Y, Wang W, Chen Y, et al. The investigation of polymer-siRNA nanoparticle for gene therapy of gastric cancer
in vitro. Int J Nanomedicine. 2010;5:129-136. https://doi.org/10.2147/IJN.S8503
28. Chen Y, Lian G, Liao C, et al. Characterization of polyethylene glycol-grafted polyethylenimine and superparamag-
netic iron oxide nanoparticles (PEG-g-PEI-SPION) as an MRI-visible vector for siRNA delivery in gastric cancer in
vitro and in vivo. J Gastroenterol. 2013;48(7):809-821. https://doi.org/10.1007/s00535-012-0713-x
29. Peng H, Yang H, Song L, et al. Sustained delivery of siRNA/PEI complex from in situ forming hydrogels potently
inhibits the proliferation of gastric cancer. J Exp Clin Cancer Res. 2016;35(1):57. https://doi.org/10.1186/s13046-
016-0334-y
30. Huo J. Effects of chitosan nanoparticle-mediated BRAF siRNA interference on invasion and metastasis of gastric
cancer cells. Artif Cells Nanomed Biotechnol. 2016;44(5):1232-1235. https://doi.org/10.3109/21691401.2015.1019666
31. Sadio A, Gustafsson JK, Pereira B, et al. Modified-chitosan/siRNA nanoparticles downregulate cellular CDX2 expres-
sion and cross the gastric mucus barrier. PLoS One. 2014;9(6):e99449. https://doi.org/10.1371/journal.pone.0099449
https://doi.org/10.1016/j.biopha.2023.115927
https://doi.org/10.3390/cancers16111958
https://doi.org/10.3389/fonc.2024.1333623
https://doi.org/10.1016/j.esmoop.2023.102226
https://doi.org/10.1016/j.esmoop.2023.102226
https://doi.org/10.5230/jgc.2025.25.e10
https://doi.org/10.1097/MS9.0000000000003608
https://doi.org/10.1007/s11864-025-01300-0
https://doi.org/10.3389/fonc.2025.1654300
https://doi.org/10.1007/s11096-025-02055-2
https://doi.org/10.3390/biomedicines12092001
https://doi.org/10.1016/j.jgeb.2025.100484
https://doi.org/10.1111/imr.12046
https://doi.org/10.3389/fmolb.2021.643657
https://doi.org/10.1080/10409238.2020.1738331
https://doi.org/10.1146/annurev-biophys-083012-130404
https://doi.org/10.1146/annurev-biophys-083012-130404
https://doi.org/10.1080/21691401.2017.1307210
https://doi.org/10.3390/ph15101295
https://doi.org/10.3389/fbioe.2025.1565999
https://doi.org/10.1038/s41598-025-32407-x
https://doi.org/10.26599/NBE.2024.9290086
https://doi.org/10.1080/1120009X.2024.2308980
https://doi.org/10.2147/IJN.S8503
https://doi.org/10.1007/s00535-012-0713-x
https://doi.org/10.1186/s13046-016-0334-y
https://doi.org/10.1186/s13046-016-0334-y
https://doi.org/10.3109/21691401.2015.1019666
https://doi.org/10.1371/journal.pone.0099449
96 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
G. Seifollahnezhad, B. Erdağ
32. Wu C, Zhang Y, Li F, et al. Precise engineering of cholesterol-loaded chitosan micelles as a promising nanocarrier
system for co-delivery drug-siRNA for the treatment of gastric cancer therapy. Process Biochem. 2022;120:265-274.
https://doi.org/10.1016/j.procbio.2022.05.019
33. Zhang Q, Zhang H, Ning T, et al. Exosome-delivered c-Met siRNA could reverse chemoresistance to cisplatin in
gastric cancer. Int J Nanomedicine. 2020;15:2323-2335. https://doi.org/10.2147/IJN.S231214
34. Ouyang D, Li H, Luo K, et al. Mesenchymal stem cell-derived exosomes as nanodrug carrier of doxorubicin
combined with PVT1 siRNA inhibits the progression of gastric cancer. Arab J Gastroenterol. 2025;26(2):149-156.
https://doi.org/10.1016/j.ajg.2025.01.012
35. Luo X, Peng X, Hou J, et al. Folic acid-functionalized polyethylenimine superparamagnetic iron oxide nanopar-
ticles as theranostic agents for magnetic resonance imaging and PD-L1 siRNA delivery for gastric cancer. Int
J Nanomedicine. 2017;12:5331-5343. https://doi.org/10.2147/IJN.S137245
36. Yao H, Sun L, Li J, et al. A novel therapeutic siRNA nanoparticle designed for dual-targeting CD44 and Gli1 of
gastric cancer stem cells. Int J Nanomedicine. 2020;15:7013-7034. https://doi.org/10.2147/IJN.S260163
37. Fu H, Zhang J, Chen H, et al. NPR1 promotes lipid droplet lipolysis to enhance mitochondrial oxidative phosphoryla-
tion and fuel gastric cancer metastasis. Adv Sci (Weinh). 2025;12(37):e03233. https://doi.org/10.1002/advs.202503233
38. Cheng P, Zhong Z, Wang Y, et al. Targeted inhibition of gastric cancer progression via a chitosan-RNU11 siRNA
nanoparticle delivery system: Mechanistic insights and therapeutic potential. Cancer Nanotechnol. 2025;16(1):14.
https://doi.org/10.1186/s12645-025-00311-8
39. Chen Y, Wang W, Lian G, et al. Development of an MRI-visible nonviral vector for siRNA delivery targeting gastric
cancer. Int J Nanomedicine. 2012;7:359-368. https://doi.org/10.2147/IJN.S24083
40. Zhao S, Min P, Liu L, et al. NEDD9 facilitates hypoxia-induced gastric cancer cell migration via MICAL1-related
Rac1 activation. Front Pharmacol. 2019;10:291. https://doi.org/10.3389/fphar.2019.00291
41. Li F, Shi J, Xu Z, et al. S100A4-MYH9 axis promote migration and invasion of gastric cancer cells by inducing TGF-
β-mediated epithelial-mesenchymal transition. J Cancer. 2018;9(21):3839-3849. https://doi.org/10.7150/jca.25469
42. Hong L, Qiao T, Han Y, et al. ZNRD1 mediates resistance of gastric cancer cells to methotrexate by regulation of
IMPDH2 and Bcl-2. Biochem Cell Biol. 2006;84(2):199-206. https://doi.org/10.1139/o05-173
43. Kitayama K, Yashiro M, Morisaki T, et al. Pyruvate kinase isozyme M2 and glutaminase might be promising molecu-
lar targets for the treatment of gastric cancer. Cancer Sci. 2017;108(12):2462-2469. https://doi.org/10.1111/cas.13421
44. Kim HO, Kim E, An Y, et al. A biodegradable polymersome containing Bcl-xL siRNA and doxorubicin as a dual
delivery vehicle for a synergistic anticancer effect. Macromol Biosci. 2013;13(6):745-754. https://doi.org/10.1002/
mabi.201200448
45. Huang J, Lan N, Liu M, et al. The effect of Rac1 siRNA on the biological behaviors of gastrointestinal cancer cells.
J Sichuan Univ Med Sci Ed. 2009;40(4):588-592. PMID: 19764550.
46. Zhou W, Tan W, Huang X, et al. Doxorubicin combined with Notch1 targeting siRNA for the treatment of gastric
cancer. Oncol Lett. 2018;16(3):2805-2812. https://doi.org/10.3892/ol.2018.9039
47. Zhou W, Wang J, Man WY, et al. siRNA silencing EZH2 reverses cisplatin resistance of human non-small cell lung and
gastric cancer cells. Asian Pac J Cancer Prev. 2015;16(6):2425-2430. https://doi.org/10.7314/APJCP.2015.16.6.2425
48. Xu XT, Tao ZZ, Song QB, et al. siRNA targeting decoy receptor 3 enhances the sensitivity of gastric carcinoma cells
to 5-fluorouracil. Exp Ther Med. 2012;4(3):465-468. https://doi.org/10.3892/etm.2012.606
49. Wang Q, Chen C, Xu X, et al. APAF1-binding long noncoding RNA promotes tumor growth and multi-
drug resistance in gastric cancer by blocking apoptosome assembly. Adv Sci (Weinh). 2022;9(28):2201889.
https://doi.org/10.1002/advs.202201889
50. Sun Y, Guo BF, Xu LB, et al. Stat3-siRNA inhibits the growth of gastric cancer in vitro and in vivo. Cell Biochem
Funct. 2015;33(7):495-502. https://doi.org/10.1002/cbf.3148
51. Sun P, Yu H, Zhang WQ, et al. Lentivirus-mediated siRNA targeting VEGF inhibits gastric cancer growth in vivo.
Oncol Rep. 2012;28(5):1687-1692. https://doi.org/10.3892/or.2012.1966
52. Zhang W, Jin Z, Yu Z, et al. Survivin siRNA inhibits gastric cancer in nude mice. Cell Biochem Biophys. 2012;62(2):337-
341. https://doi.org/10.1007/s12013-011-9315-0
53. Sun L, Zhang Y, Lou J. ARHGAP9 siRNA inhibits gastric cancer cell proliferation and EMT via inactivating Akt,
p38 signaling and inhibiting MMP2 and MMP9. Int J Clin Exp Pathol. 2017;10(12):11979-11986. PMID: 31966562.
54. Salman DM, Mohammad TAM. siRNA-based therapy for gastric adenocarcinoma: What’s next step? Pathol Res
Pract. 2024;258:155328. https://doi.org/10.1016/j.prp.2024.155328
Submitted: April 08, 2026
https://doi.org/10.1016/j.procbio.2022.05.019
https://doi.org/10.2147/IJN.S231214
https://doi.org/10.1016/j.ajg.2025.01.012
https://doi.org/10.2147/IJN.S137245
https://doi.org/10.2147/IJN.S260163
https://doi.org/10.1002/advs.202503233
https://doi.org/10.1186/s12645-025-00311-8
https://doi.org/10.2147/IJN.S24083
https://doi.org/10.3389/fphar.2019.00291
https://doi.org/10.7150/jca.25469
https://doi.org/10.1139/o05-173
https://doi.org/10.1111/cas.13421
https://doi.org/10.1002/mabi.201200448
https://doi.org/10.1002/mabi.201200448
https://doi.org/10.3892/ol.2018.9039
https://doi.org/10.7314/APJCP.2015.16.6.2425
https://doi.org/10.3892/etm.2012.606
https://doi.org/10.1002/advs.202201889
https://doi.org/10.1002/cbf.3148
https://doi.org/10.3892/or.2012.1966
https://doi.org/10.1007/s12013-011-9315-0
https://doi.org/10.1016/j.prp.2024.155328
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 97
Therapeutic Role of siRNA in Gastric Cancer: Gene Silencing Mechanisms and Nanocarrier-Based Delivery Strategies
Гейсар Сейфолланеждад 1, Беррин Ердаг 2, 3
1 Факультет молекулярної медицини,
Стамбульський університет Айдин, Стамбул, Турція
2 Факультет медичної біології,
Стамбульський університет Айдин, Стамбул, Турція
3 «Сенбіо Біотекнолоджі» ТОВ, Стамбул, Турція
ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА:
МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ
ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ
Рак шлунка (РШ) продовжує бути значним фактором глобальної смертності від онкологічних захворювань че-
рез пізню діагностику, гетерогенність пухлин та частий розвиток лікарської резистентності. Незважаючи на
досягнення в хірургічних методах, хіміотерапії, таргетній терапії та імунотерапії, довгострокові показники ви-
живаності залишаються незадовільними, що вказує на необхідність інноваційних, молекулярно-орієнтованих
підходів. Малі інтерферуючі РНК (siРНК) стали перспективними інструментами пригнічення генів, здатними
вибірково пригнічувати експресію онкогенних драйверів та сигнальні шляхи, пов’язані з резистентністю, через
механізми РНК-інтерференції. Доклінічні дослідження на моделях РШ демонструють ефективність пригнічен-
ня siРНК різних молекулярних мішеней, включаючи CD44v6, Rac1 та ZNRD1, що приводить до гальмування
проліферації клітин, пригнічення міграції та інвазії, посилення апоптозу та підвищення чутливості до хіміо-
препаратів. Однак успішне впровадження стратегій на основі siРНК в клінічну практику залежить від розроб-
ки ефективних та безпечних систем доставки. Нещодавні досягнення в нанотехнологіях сприяли створенню
багатофункціональних наноносіїв, таких як наночастинки на основі ліпідів, системи на основі пептидів, плат-
форми, отримані з хітозану, везикули, що міметують екзосоми, конструкції пошарової зборки та тераностичні
наночастинки, що реагують на стимули. Ці сконструйовані платформи розроблено для підвищення стабільнос-
ті siРНК, покращення таргетування пухлини, полегшення внутрішньоклітинного транспорту та сприяння ви-
ходу з ендосом, мінімізуючи при цьому вплив поза цільовою зоною та імунну активацію. Доклінічні результати
свідчать про значний біологічний потенціал; однак, необхідні додаткові дослідження для вирішення питань
біорозподілу, безпеки, масштабованості та регуляторної стандартизації перед клінічним застосуванням. Зага-
лом, стратегії на основі siРНК можуть відігравати вирішальну роль у майбутньому розвитку персоналізованих
терапевтичних структур у дослідженнях РШ. Цей огляд підкреслює необхідність інтегрувати вибір молекуляр-
них мішеней з розробкою систем доставки в контексті, специфічному для РШ, що забезпечить трансляційно
релевантні перспективи.
Ключові слова: siРНК, рак шлунка, пригнічення генів, доставка наноносіїв, РНК-інтерференція.
|
| id | oai:ojs2.ex.aqua-time.com.ua:article-639 |
| institution | Experimental Oncology |
| issn | 2312-8852 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-22T01:00:30Z |
| publishDate | 2026 |
| publisher | PH Akademperiodyka |
| record_format | ojs |
| resource_txt_mv | exp-oncologycomua/94/319156457617adb2a4a061c4777f8494.pdf |
| spelling | oai:ojs2.ex.aqua-time.com.ua:article-6392026-08-21T12:36:20Z THERAPEUTIC ROLE OF siRNA IN GASTRIC CANCER: GENE SILENCING MECHANISMS AND NANOCARRIER-BASED DELIVERY STRATEGIES ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ Seifollahnezhad , Gheysar Erdağ, Berrin siРНК, рак шлунка, пригнічення генів, доставка наноносіїв, РНК-інтерференція siRNA, gastric cancer, gene silencing, nanocarrier delivery, RNA interference Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diagnoses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, long-term survival rates remain unsatisfactory, underscoring the need for innovative, molecularly driven approaches. SiRNA has emerged as a promising gene-silencing tool capable of selectively downregulating oncogenic drivers and pathways associated with resistance via RNA interference. Preclinical studies using GC models demonstrate promising biological activity following siRNA-mediated suppression of various molecular targets — including CD44v6, Rac1, and ZNRD1—leading to reduced cell proliferation, inhibited migration and invasion, enhanced apoptosis, and increased chemosensitivity. However, the successful translation of siRNA-based strategies into clinical practice is fundamentally reliant on the development of efficient and safe delivery systems. Recent advancements in nanotechnology have enabled the development of multifunctional nanocarriers, including lipid-based nanoparticles, peptide-based systems, chitosanderived platforms, exosome-mimetic vesicles, layer-by-layer architectures, and stimuli-responsive theranostic nanoparticles. These engineered platforms are designed to enhance siRNA stability, improve tumor targeting, facilitate intracellular trafficking, and promote endosomal escape while minimizing off-target effects and immune activation. Preclinical findings suggest significant biological potential; however, additional research is required to address issues concerning biodistribution, safety, scalability, and regulatory standardization before clinical application. Overall, siRNA-based strategies may play a crucial role in the future development of precision-oriented therapeutic frameworks in GC research. Importantly, this review emphasizes the integration of molecular target selection with delivery system design in a GC-specific context. By systematically linking validated siRNA targets with corresponding nanocarrier strategies, this work provides a more application-oriented and translationally relevant perspective that is not typically addressed in conventional RNA interference or nanocarrier-focused reviews. Рак шлунка (РШ) продовжує бути значним фактором глобальної смертності від онкологічних захворювань через пізню діагностику, гетерогенність пухлин та частий розвиток лікарської резистентності. Незважаючи на досягнення в хірургічних методах, хіміотерапії, таргетній терапії та імунотерапії, довгострокові показники виживаності залишаються незадовільними, що вказує на необхідність інноваційних, молекулярно-орієнтованих підходів. Малі інтерферуючі РНК (siРНК) стали перспективними інструментами пригнічення генів, здатними вибірково пригнічувати експресію онкогенних драйверів та сигнальні шляхи, пов’язані з резистентністю, через механізми РНК-інтерференції. Доклінічні дослідження на моделях РШ демонструють ефективність пригнічення siРНК різних молекулярних мішеней, включаючи CD44v6, Rac1 та ZNRD1, що приводить до гальмування проліферації клітин, пригнічення міграції та інвазії, посилення апоптозу та підвищення чутливості до хіміопрепаратів. Однак успішне впровадження стратегій на основі siРНК у клінічну практику залежить від розробки ефективних та безпечних систем доставки. Нещодавні досягнення в нанотехнологіях сприяли створенню багатофункціональних наноносіїв, таких як наночастинки на основі ліпідів, системи на основі пептидів, платформи, отримані з хітозану, везикули, що міметують екзосоми, конструкції пошарової зборки та тераностичні наночастинки, що реагують на стимули. Ці сконструйовані платформи розроблено для підвищення стабільності siРНК, покращення таргетування пухлини, полегшення внутрішньоклітинного транспорту та сприяння виходу з ендосом, мінімізуючи при цьому вплив поза цільовою зоною та імунну активацію. Доклінічні результати свідчать про значний біологічний потенціал; однак необхідні додаткові дослідження для вирішення питань біорозподілу, безпеки, масштабованості та регуляторної стандартизації перед клінічним застосуванням. Загалом, стратегії на основі siРНК можуть відігравати вирішальну роль у майбутньому розвитку персоналізованих терапевтичних стратегій у дослідженнях РШ. Цей огляд підкреслює необхідність інтегрувати вибір молекулярних мішеней з розробкою систем доставки в контексті, специфічному для РШ, що забезпечить трансляційно релевантні перспективи. PH Akademperiodyka 2026-08-21 Article Article application/pdf https://exp-oncology.com.ua/index.php/Exp/article/view/639 10.15407/exp-oncology.2026.02.081 Experimental Oncology; Vol. 48 No. 2 (2026): Experimental Oncology; 81-97 Експериментальна онкологія; Том 48 № 2 (2026): Експериментальна онкологія; 81-97 2312-8852 1812-9269 10.15407/exp-oncology.2026.02 en https://exp-oncology.com.ua/index.php/Exp/article/view/639/469 Copyright (c) 2026 Experimental Oncology https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| spellingShingle | siРНК рак шлунка пригнічення генів доставка наноносіїв РНК-інтерференція Seifollahnezhad , Gheysar Erdağ, Berrin ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ |
| title | ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ |
| title_alt | THERAPEUTIC ROLE OF siRNA IN GASTRIC CANCER: GENE SILENCING MECHANISMS AND NANOCARRIER-BASED DELIVERY STRATEGIES |
| title_full | ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ |
| title_fullStr | ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ |
| title_full_unstemmed | ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ |
| title_short | ТЕРАПЕВТИЧНА РОЛЬ siРНК ПРИ РАКУ ШЛУНКА: МЕХАНІЗМИ САЙЛЕНСИНГУ ГЕНІВ ТА СТРАТЕГІЇ ДОСТАВКИ НА ОСНОВІ НАНОНОСІЇВ |
| title_sort | терапевтична роль siрнк при раку шлунка: механізми сайленсингу генів та стратегії доставки на основі наноносіїв |
| topic | siРНК рак шлунка пригнічення генів доставка наноносіїв РНК-інтерференція |
| topic_facet | siРНК рак шлунка пригнічення генів доставка наноносіїв РНК-інтерференція siRNA gastric cancer gene silencing nanocarrier delivery RNA interference |
| url | https://exp-oncology.com.ua/index.php/Exp/article/view/639 |
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