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From Antibody Drugs to RNA Interference and Nanotherapy: The Evolution and Integration of Targeted Strategies in Gastric Cancer
Authors Wang S, Dong Y, Ma L 
, Wu J, Long D, Mei Z , Jiang C, Lyu X
Received 22 April 2026
Accepted for publication 26 June 2026
Published 22 July 2026 Volume 2026:21 618409
DOI https://doi.org/10.2147/IJN.S618409
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Yan Shen
Songlin Wang,1,* Yinhong Dong,1,* Lan Ma,2– 4,* Jiangfeng Wu,2– 4 Daoguo Long,1 Zhao Mei,5,6 Chuanlin Jiang,1 Xiaoguang Lyu1,7
1Zhongxiang People’s Hospital, Zhongxiang, People’s Republic of China; 2Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, People’s Republic of China; 3College of Basic Medical Science, China Three Gorges University, Yichang, People’s Republic of China; 4Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, Yichang, People’s Republic of China; 5Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University, Yichang, People’s Republic of China; 6Department of Pharmacy, Yichang Central People’s Hospital, Yichang, People’s Republic of China; 7Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chuanlin Jiang, Email [email protected] Xiaoguang Lyu, Email [email protected]
Abstract: Gastric cancer is a leading cause of cancer death worldwide. Targeted therapy is shifting from blocking signaling pathways to precise gene regulation. This review covers three key areas: antibody drugs, RNAi, and nanocarriers. Anti-HER2 agents, VEGFR2 inhibitors, Claudin 18.2-directed therapies and PD-1/PD-L1 inhibitors improve survival in biomarker-selected patients—but resistance and low response rates (ORR < 20% in unselected groups) limit their use. RNAi silences key oncogenes to reverse chemoresistance and reprogram the immunosuppressive tumor microenvironment, but it suffers from rapid degradation, poor endosomal escape, off-target effects, and weak tumor penetration. Nanocarrier systems—including lipid nanoparticles (LNPs), stimuli-responsive micelles, and mesoporous silica—combined with aptamers enable targeted delivery of therapeutic antibodies and siRNA, penetration across stromal barriers, and controlled, tumor microenvironment–triggered cargo release. Altogether, the future of gastric cancer therapy is moving beyond monotherapy to a five-part strategy: antibody targeting, RNA silencing, nanocarrier delivery, AI-guided decisions, and immune remodeling.
Keywords: gastric cancer, target therapy, RNA interference, siRNA, shRNA, nanoparticles
Gastric cancer remains a significant global health challenge—it is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide, with 684,000 lives lost in 2022 (GLOBOCAN).1 In China, gastric cancer is the third in incidence and the second in mortality—accounting for 478,000 new cases and 373,000 deaths annually.2,3 Due to its asymptomatic nature in the early stage, 70% of patients are diagnosed at advanced stage, resulting in a five-year overall survival rate of less than 10%.4–7 These figures underscore an urgent need for more effective therapies to delay tumor progression and extend survival time.
Antibody-based drugs launched targeted therapy for gastric cancer. Trastuzumab validated HER2, ramucirumab enabled anti-angiogenesis, and immune checkpoint inhibitors achieved durable responses in biomarker-selected patients.8–11 But resistance—due to target loss, pathway redundancy, or immune evasion—and low response rates in unselected patients remain key challenges. 10 RNA interference (RNAi) offers the capacity to silence pathogenic genes at the mRNA level.12 In gastric cancer, siRNAs directed against HER2, c-MET, or KRAS mutants have shown promising results in preclinical studies. 13 The translational barrier, however, is delivery: naked nucleic acids are rapidly degraded, poorly internalized, and prone to off-target effects.12,13 It is here that nanotechnology becomes indispensable. Nanocarriers—such as lipid nanoparticles and polymeric micelles—protect siRNA from degradation, enhance cellular uptake, and enable controlled release.14,15 They can also penetrate the dense gastric tumor stroma and respond to microenvironmental cues like low pH or elevated enzyme levels.14,16 Most promising is delivering antibodies and siRNA in the nanocarrier to combine extracellular targeting with intracellular gene silencing.13,17–19
This review traces the evolution from antibody drugs to RNAi and nanotherapeutics in gastric cancer. We argue that monotherapy is inherently limited and that the future lies in synergistic integration: antibodies for targeting, RNAi for gene silencing, and nanotechnology for precision delivery.14,16
Clinically Validated Molecular Targets in Gastric Cancer for Targeted Therapy and Immunotherapy (Table 1)
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Table 1 Gastric Cancer Targeted Drugs Currently Under Clinical Investigation |
The Following are the Crucial Molecular Targets
Targeting the HER2 Receptor
HER2 (ErbB2), a ligand-independent receptor tyrosine kinase, preferentially heterodimerizes with HER3 or EGFR, triggering constitutive activation of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways in the absence of ligand binding.37–41 These cascades promote cell survival, proliferation, and immune evasion through effectors including mTORC1, Elk-1, c-Myc, and STAT3.42
PI3K/AKT/mTOR Pathway
When HER2 heterodimerizes with HER3, it recruits and phosphorylates the PI3K regulatory subunit, thereby activating the enzyme. Activated PI3K converts PIP2 to PIP3, which recruits and activates AKT (protein kinase B). AKT then promotes cell survival and suppresses apoptosis by phosphorylating key targets—including BAD and caspase-9—and enhancing pro-survival signaling.43–45 AKT also activates mTORC1, driving protein synthesis, cell growth, proliferation, and metabolic adaptation.46–48
RAS/RAF/MEK/ERK Pathway
HER2 activation recruits Grb2-SOS complex, triggering RAS activation. Active RAS activates RAF (MAPKKK), which phosphorylates and activates MEK (a MAPKK); MEK then phosphorylates and activates ERK (a MAPK). Nuclear translocation of activated ERK leads to phosphorylation of transcription factors—including Elk-1, c-Fos, and c-Myc—driving G1-to-S-phase cell cycle progression, proliferation, differentiation, and motility.46,49 Both pathways also phosphorylate STAT3, thereby modulating JAK/STAT signaling to promote immune evasion and reshape the tumor microenvironment.50
Both pathways phosphorylate STAT3, thus modulating JAK/STAT signaling to promote immune evasion and reshape the tumor microenvironment.46,50
Targeting the VEGF Receptor (VEGFR)
The VEGF family includes VEGF-A, VEGF-C, and VEGF-D. VEGF-A drives angiogenesis via VEGFR-1/VEGFR-2 (KDR); VEGF-C/VEGF-D drive lymphangiogenesis via VEGFR-3.10 In gastric cancer, VEGF-A and VEGFR-2 are overexpressed relative to adjacent normal tissue and correlate with microvessel density (MVD). This promotes leaky vasculature, fueling hypoxia, acidosis, invasion, and metastasis: high MVD supports tumor growth and spread—VEGF enhances permeability to facilitate intravasation; VEGF-C/VEGFR-3 drives lymphangiogenesis and lymph node metastasis. VEGF also induces an immunosuppressive microenvironment by impairing dendritic cell maturation and T-cell infiltration, expanding Tregs, and upregulating PD-L1—contributing to “cold tumor” resistance to checkpoint inhibitors.10,51,52 Consequently, targeting VEGF/VEGFR (eg, fruquintinib [FRUTIGA trial, HR 0.67] and surufatinib) improves survival in heavily pretreated Chinese patients.53
Targeting the Claudin 18.2
CLDN18.2 is a tight junction protein normally confined to the apical surface of gastric epithelial cells, maintaining epithelial barrier integrity and polarity.30,54 In gastric cancer, loss of polarity exposes it across the entire tumor cell membrane—converting it from an immunologically “hidden” to a “conspicuous” target.5,55 Epigenetic derepression drives its overexpression: promoter hypomethylation lifts transcriptional silencing, enabling stable, high-level expression. This fuels oncogenesis via three key mechanisms: (1) PI3K/AKT activation → suppressed apoptosis and enhanced survival/proliferation; (2) ERK/MAPK-driven AP-1 activation → upregulation of cell-cycle genes; and (3) CLDN18-ARHGAP26 fusion (in ~15% of diffuse-type cases) → constitutive RhoA activation, cytoskeletal remodeling, increased motility, EMT, and invasion. CLDN18.2+ tumors also create an immunosuppressive microenvironment—recruiting Tregs, M2 macrophages, and MDSCs; impairing dendritic cell maturation and T-cell infiltration; and disrupting antigen presentation—enabling immune escape.56,57 Critically, its stable epigenetic expression—and selective pressure in metastatic niches—elevates CLDN18.2 in metastases, reinforcing its value as a metastatic target.54,58 Clinically, zolbetuximab + chemotherapy improved PFS (7.5 vs 5.3 mo) and OS (14.4 vs 12.2 mo) in SPOTLIGHT and GLOW trials, leading to FDA/NMPA approval in 2024.30,31 Claudin 18.2–directed CAR-T (CT053) achieved a 57.1% ORR in heavily pretreated patients.
Target of Immune Checkpoint Inhibitor Therapy
PD-1/PD-L1
In gastric adenocarcinoma, PD-L1 is upregulated by inflammatory cytokines—including IFN-γand IL-6—via JAK/STAT and NF-κB signaling, enabling immune evasion. Approximately 10% of cases are EBV-positive; these tumors consistently overexpress PD-L1 and show enhanced response to PD-1 blockade. PD-1 is expressed on T cells, B cells, and NK cells, whereas its ligand PD-L1 is upregulated on tumor cells and antigen-presenting cells (eg, macrophages, dendritic cells). PD-1/PD-L1 binding recruits SHP-1 and SHP-2 phosphatases, inhibiting TCR signaling—thereby suppressing T-cell proliferation, cytokine production (IFN-γ, IL-2), and effector function—and facilitating tumor immune escape.59
Analysis of the Current Limitations in Targeted Therapy for Gastric Cancer
Dependence on Specific Target Expression
Targeted therapy requires uniform, high-level expression of tumor-specific markers—but many gastric cancers show low or heterogeneous expression. For example, only 7.3–20.2% of patients overexpress HER2, typically in focal, intensely stained regions.60 Claudin 18.2 positivity varies widely (30–70%) depending on the IHC assay and cutoff: early studies using the 43–14A antibody reported >60% positivity, whereas the VENTANA SP97 assay (≥2+in ≥75%) yields 35–50% in both Western and Asian cohorts.61 This variability underscores the urgent need for standardized, companion diagnostic—approved testing.
Prominent Drug Resistance Challenges
Targeted therapies face primary and secondary resistance. Primary resistance arises from compensatory pathway activation (eg, MAPK, PI3K/AKT) or baseline mutations; secondary resistance stems from acquired target-gene mutations (eg, HER2 L755S/V777L), phenotypic shifts, epigenetic changes, or co-amplifications (MYC, CCNE1, CDK12).62–65 For example, trastuzumab resistance often involves HER2 alterations, IGF-1R upregulation, or bypass signaling via MET/FGFR. Apatinib may promote immune evasion by activating MAPK or inhibiting STAT3/PKM2.64–66 VEGF further contributes to a “cold tumor” microenvironment by impairing dendritic cell maturation and T-cell infiltration while expanding Tregs.67
Abnormal Tumor Vasculature
Tumor blood vessels are chaotic, tortuous, leaky, and dysfunctional—causing poor drug delivery and an immunosuppressive microenvironment. Hypoxia from abnormal perfusion recruits immunosuppressive cells and factors, impairing immune cell infiltration and function. Anti-VEGF agents (eg, ramucirumab, apatinib) were initially intended to “starve” tumors. However, short-term, moderate VEGF inhibition could induce transient “vascular normalization”—a temporary restoration of vessel structure and function. Yet this window is narrow, dynamic, and highly variable across patients, making it hard to identify and easy to miss clinically. Moreover, tumors rapidly activate bypass pathways (eg, FGF, Angiopoietin) upon VEGF blockade, driving vascular regrowth and undermining combination therapy. This adaptation not only reduces efficacy but may also promote a more invasive phenotype.
Safety Concerns
Some targeted agents cause significant toxicities. Topoisomerase inhibitors like exatecan induce grade ≥3 neutropenia in 20–30% of patients.68 CCR8×CLDN18.2 bispecific antibodies (eg, LM-108) are still in early development; their long-term safety and efficacy remain undefined. Bemarituzumab causes vision impairment, dry eye, or corneal damage in >25% of patients—mostly reversible but potentially affecting adherence.69 Long-term data on Claudin 18.2-targeted therapies are scarce, so the risks of chronic toxicities (eg, interstitial lung disease) are unclear.
Economic and Accessibility Barriers
High treatment costs limit the broad use of targeted therapies. Trastuzumab costs over 300,000 yuan annually; CAR-T therapy—typically priced above 1 million yuan per treatment—presents a substantially higher financial barrier, critically constraining patient access. So far, only one Claudin 18.2-targeted agent, zolbetuximab (not trastuzumab), has received global marketing approval; ADCs and CAR-T therapies remain under clinical investigation. First-line guidelines increasingly recommend “targeted therapy + immunotherapy + chemotherapy”—a regimen far costlier than chemotherapy alone. Biomarker testing (eg, for Claudin 18.2) adds further financial strain.
RNA Interference (RNAi) Technology Demonstrates Significant Potential in the Field of Gastric Cancer Therapy (Table 2); However, It Also Encounters Various Challenges
Key Advantages of RNAi-Based Therapeutic Approaches in Gastric Cancer Management
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Table 2 Recent Advances in Experimental Research on RNAi Therapy for Gastric Cancer |
2) This technology effectively addresses drug resistance commonly encountered in conventional therapies. For example, knockdown of the lncRNA NCK-AS1 reverses cisplatin resistance and improves chemotherapeutic sensitivity.106 Targeting the E3 ubiquitin ligase SYVN1 has also been shown to significantly inhibit gastric cancer cell (GC cell) proliferation.107
3) RNAi technology demonstrates the capacity to modulate the tumor microenvironment (TME). Silencing of the NAT10 gene interrupts the CXCL2/STAT3 signaling axis, thereby suppressing M2 macrophage polarization—with the proportion of M2 macrophages in liver metastases declining from 42% to baseline levels—resulting in a 78% reduction in liver metastasis.108 Furthermore, the novel delivery system TMAB3, which carries a RIG-I agonist RNA, enhances CD8⁺ T cell infiltration and effectively reverses the “cold tumor” phenotype, thereby augmenting anti-tumor immune responses.109
4) The technology is associated with low toxicity and minimal side effects. For example, under physiological conditions, AE1 is exclusively expressed in red blood cells, and siRNA delivery vehicles are unable to cross the bone marrow-blood barrier (MBB).105 Consequently, no hemolytic or hepatorenal toxicities were observed in preclinical animal studies.
Current Challenges and Limitations of RNAi Therapy
1) Instability of RNA molecules: Unprotected RNA is highly susceptible to degradation by endogenous nucleases in vivo, leading to a short half-life in blood and tissues. This instability prevents the maintenance of sustained therapeutic concentrations, thereby compromising treatment efficacy.110–112
2) Suboptimal delivery efficiency: Conventional delivery systems—such as liposomes—exhibit limited targeting specificity. The lack of highly efficient and selective delivery platforms hinders the precise accumulation of RNAi molecules at tumor sites, thereby constraining their broad clinical applicability.100 Consequently, numerous studies are currently focused on developing highly specific, tumor-targeted delivery systems—including aptamers and nanoparticles—to enhance the efficient delivery of siRNA and shRNA to tumor sites (Figure 1 and Table 3).111,113–115 Tumor-targeted lipid nanoparticles (such as Onpattro-like platforms) and GalNAc-conjugated siRNAs are currently undergoing phase I/II trials for solid tumors. Aptamer-siRNA chimeras specific to gastric cancer and pH-responsive nanoparticles have achieved over 50-fold tumor enrichment in orthotopic models.
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Table 3 Recent Advances in Experimental Research on Targeted Delivery of siRNA and shRNA for RNAi Therapy in Gastric Cancer |
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Figure 1 Targeted delivery systems, such as aptamers and nanoparticles, improve the efficient and precise delivery of siRNA to tumor sites, thereby enhancing therapeutic efficacy and enabling potent antitumor effects. |
3) Potential off-target effects: RNAi molecules may hybridize with non-target mRNA sequences, leading to unintended gene silencing and posing potential risks of adverse physiological effects.115,122
4) Immune activation potential: Exogenous RNA can activate the innate immune system, inducing the production of inflammatory mediators that may compromise both the safety and tolerability of RNAi-based therapies.122
5) Production complexity and cost constraints: The synthesis, purification, and quality control of RNAi therapeutics involve technically demanding processes, contributing to high manufacturing costs. These challenges hinder large-scale production and widespread clinical adoption. Moreover, complementary genetic testing (eg, assessment of NAT10 and KLF5 expression levels) imposes additional economic and therapeutic burdens on patients.
6) Inadequate long-term safety data: The majority of current evidence is derived from animal models, and comprehensive long-term safety evaluations in humans—particularly regarding immunogenicity and organ-specific accumulation—remain lacking.122 Furthermore, epigenetic targets such as NAT10 may disrupt normal RNA modification pathways in healthy cells, raising concerns about potential yet undefined biological risks.
Nanoparticle-Based Therapeutics for Gastric Cancer: Advancing from Passive Targeting to Intelligent, Multimodal Synergy
Evolution of Targeting Strategies: From Active Targeting to Microenvironment-Responsive Delivery
Conventional passive targeting relies on the enhanced permeability and retention (EPR) effect. However, EPR effect is highly heterogeneous across and within gastric tumors, limiting its reliability. To improve targeting, nanoparticles are surface-modified with ligands—such as folate, transferrin, antibodies, or aptamers—that bind receptors overexpressed on GC cells. For example, folate receptor alpha (FR ɑ) is overexpressed in >60% of gastric cancers; folate-conjugated nanoparticles increase tumor accumulation 3-5-fold compared with non-targeted controls in mouse models.123 Microenvironment-responsive nanoparticles offer greater precision: they release drug only in response to gastric tumor-specific cues—such as low pH (6.0–6.8), high GSH concentrations (2–10 mM), elevated ROS, or overexpression of matrix metalloproteinases MMP-2 and MMP-9—using cleavable linkers like hydrazone, disulfide, or thioacetal bonds. A pH/ROS dual-responsive docetaxel nanomicelle achieved 79.6% tumor growth inhibition in subcutaneous gastric cancer xenografts—significantly higher than that of free docetaxel.124
Overcoming Chemotherapy Resistance: From Gene Silencing to Pathway Intervention
Chemotherapy resistance is a major cause of treatment failure in gastric cancer. Nanoparticles can deliver both chemotherapeutic drugs and gene therapeutics—such as siRNA, miRNA, or CRISPR-Cas systems—to reverse resistance at its source. Two key strategies are employed: (1) Gene silencing—target ABC transporters (eg, P-gp) or anti-apoptotic proteins (eg, Survivin, Bcl-2); and (2) Pathway inhibition—block pro-survival signals such as Notch, Wnt/β-catenin, or NF-κB. For example, liposomal nanoparticles co-delivering P-gp siRNA and paclitaxel reduced the IC50 by ~80% in resistant SGC7901/VCR cells.125 Similarly, SPIONs functionalized with the WSGC peptide inhibited Notch signaling, suppressing tumor growth by >60% and enhancing apoptosis in xenografts.123
Emerging Physical Therapies for Cancer Treatment: Integrating Photothermal Therapy, Ferroptosis Induction, and Immunomodulation
Nanoparticles serve as programmable theranostic platforms—functioning either as photonic energy transducers or as precision inducers of regulated cell death.
Photothermal Therapy (PTT)
Carbon quantum dots, MXene, and polydopamine nanoparticles absorb near-infrared light (808 nm or 1064 nm) to generate heat, raising tumor temperature above 50 °C and killing cancer cells. Limitation: poor tissue penetration limits their use in deep gastric tumors or peritoneal metastases.126,127
Ferroptosis Therapy
Nanoparticles deliver Fe2⁺/Fe3⁺ or inhibit GPX4, thereby inducing lipid peroxidation and ferroptosis. The biomimetic nanocrystal TRNC@P+L co-delivers chemotherapeutic drugs and ferroptosis inducers, showing synergistic efficacy in preclinical models of gastric cancer peritoneal metastasis.128
Immunomodulatory Nanoparticles
In a gastric carcinoma mouse model, M2pep-Cs NPs/Plerixafor nanoparticles suppress tumor progression by concurrently blocking the CXCL12-CXCR4 axis and reprogramming tumor-associated macrophages (TAMs)—specifically shifting them from immunosuppressive M2 phenotype to immunostimulatory M1 phenotypes—which enhances T-cell infiltration, activation, and tumor antigen recognition.129
Nanometer-Scale Chemotherapeutic Agents: Advancing Therapeutic Efficacy While Minimizing Systemic Toxicity
The real-world study of NPMP (paclitaxel nanomicelles) combined with immunotherapy and chemotherapy—though non-randomized and uncontrolled—achieved an objective response rate (ORR) of 42.4%, exceeding the typical ORR of 25–35% observed with conventional chemotherapy. Neutropenia rates did not increase significantly compared with historical controls, suggesting that the nanomicellar formulation improves the therapeutic index through tumor-selective drug accumulation.130 SN BioScience has received FDA Orphan Drug Designation for SNB-101 in gastric cancer—the third such designation for this novel nanoparticle formulation of SN-38. As the world’s first polymer-based nanoparticle formulation of the highly water-insoluble anticancer agent SN-38, SNB-101 is designed to enhance efficacy and reduce toxicity. The designation addresses a critical unmet medical need in gastric cancer, where advanced disease has limited treatment options and a 5-year survival rate of only 36%.
Future Development of Gastric Cancer Treatment (Figure 2)
Future directions in gastric cancer treatment focus on four key areas: 1) Precision oncology: Multi-omics profiling (genomics, proteomics, metabolomics) identifies targetable molecular drivers; CRISPR/Cas9 and animal models validate function and therapeutic potential; resulting agents—small molecules, mAbs, or bispecific antibodies—are matched to patients’ molecular profiles (eg, mutations, protein expression, immune contexture) for stratified therapy. 2) Next-generation ADCs: Optimized DAR, cleavable/conditionally active linkers, and novel payloads improve tumor selectivity and safety; rational combinations—eg, with chemo, immunomodulators, or dual-target inhibitors—overcome resistance and broaden indications. 3) CLDN18.2-directed CAR-T: Now in randomized clinical trials (eg, CT041-ST-01), this “living drug” bypasses vascular dependence, enabling direct tumor cell killing. It shows durable survival benefit after standard therapy failure, with manageable CRS and no neurotoxicity in trials. Limitations remain: strict CLDN18.2+ selection (≥40% tumor cells), complex manufacturing/logistics, high cost, and persistent challenges of solid tumors—including immunosuppressive microenvironments and target heterogeneity.
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Figure 2 Trends in the Development of Targeted Therapy for Gastric Cancer. |
Systemic therapy for gastric cancer has evolved from sequential monotherapy to rational combinations of immune checkpoint inhibitors, targeted agents, and chemotherapy. Aptamer- and nanocarrier-based delivery platforms represent a paradigm shift—enabling spatiotemporally controlled treatment, not merely incremental improvement. Current standard therapies (eg, anti-HER2, CLDN18.2-targeted, and dual PD-1/CTLA-4 blockade) provide clinical benefit but suffer from narrow therapeutic indices due to on-target/off-tumor toxicity. Aptamers—synthetic, high-affinity, low-immunogenicity nucleic acid ligands—precisely target gastric cancer drivers. Nanocarriers exploit both passive (enhanced permeability and retention, EPR) and active (ligand-mediated) tumor accumulation and release their payloads selectively in response to the tumor microenvironment—within the tumor parenchyma or the immunosuppressive stroma. Integrating these modalities enables intelligent nanosystems: either for localized intraperitoneal delivery or as multi-epitope tandem aptamer–drug conjugates (ADCs) that address gastric cancer’s core challenges—inter- and intra-tumoral heterogeneity and its strong propensity for peritoneal dissemination. This dual-strategy approach tackles three key clinical challenges in peritoneal metastases: (1) poor drug accumulation due to low peritoneal–plasma barrier permeability; (2) emergence of therapy-resistant clones under single-target treatment; and (3) systemic toxicities that limit dose intensity and duration. Clinical translation requires solving three hurdles: aptamer degradation by nucleases in vivo, RES-mediated nanoparticle clearance, and scalable GMP-compliant manufacturing with strict quality control. A phaseItrial of this aptamer-nanocarrier platform in gastric cancer patients with peritoneal metastases is expected within five years. Primary endpoints include safety plus quantitative pharmacodynamic biomarkers—tumor-to-plasma drug ratio, target saturation kinetics, and spatially resolved intratumoral payload distribution. Critically, these mechanistic metrics—not just response rates—will determine whether the platform evolves from innovation to standard therapy.
The aptamer-nanodrug system’s key advantage in gastric cancer treatment is not antibody replacement, but programmable, precise targeting. Unlike antibodies, aptamers can both bind targets and execute logic operations—eg, releasing drugs in response to tumor microenvironment cues—via rational structural design. Yet current research focuses excessively on aptamer loading onto nanoparticles, overlooking a fundamental question: What target profiles do distinct gastric cancer molecular subtypes actually require? Future progress depends less on generating more aptamers and more on establishing a clinical-translational paradigm: begin with molecular subtyping, reverse-define target requirements, then custom-design the aptamer–nanoparticle system. Critically, this system must integrate into a closed loop with liquid biopsy–based early detection and post-surgical minimal residual disease monitoring—to translate precise targeting into real survival benefits.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (Grant number [81670555]); State Key Laboratory of Medical Molecular Biology (Grant number [State Key Laboratory Special Fund 206024]); 2025 Yichang Medical and Health Research Project (No. A25-2-178); Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province (No. CXPJJH125001-2509).
Since English is not our native language, the article was refined with the assistance of Youdao Translate (Version: 11.0.0).
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no conflicts of interest.
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