Natural product-based nanoengineering in gastrointestinal stromal tumors: early promise and translational challenges

Gastrointestinal stromal tumor (GIST) remains a clinically challenging malignancy because recurrence, metastatic progression, and resistance to tyrosine kinase inhibitors (TKIs) continue to limit durable disease control (1,2). In this context, nanotechnology has emerged as a potentially useful strategy to improve therapeutic precision and complement existing targeted approaches (3).

Among nanomaterials explored for oncologic applications, zinc oxide nanoparticles (ZnO NPs) have attracted increasing attention because of their intrinsic ability to induce reactive oxygen species (ROS), promote oxidative stress, and modulate apoptosis-related signaling pathways (4-6). Over the past several years, multiple ZnO-based nanocomposite platforms have been developed and evaluated across different tumor models, as summarized in Table 1. However, this literature remains dominated by non-GIST settings, particularly epithelial tumor models, with only limited mesenchymal examples such as osteosarcoma. In this context, the extension of ZnO-based strategies to GIST, as reported by Ye et al. (16), represents a conceptually interesting expansion into a less explored disease context. Accordingly, Table 1 is intended to highlight broader mechanistic and translational themes that may inform future work in GIST. At present, however, the study by Ye et al. is best interpreted as an early proof-of-concept with limited GIST specificity.

In their recent study, Ye et al. constructed a multifunctional nanocomposite, ZnO@CS-baicalein/Au NPs, by decorating gold nanoparticles onto baicalein/chitosan-modified ZnO nanoparticles (16). This hybrid design integrates a natural flavonoid with known biological activity (17), a redox-active ZnO scaffold, and gold nanoparticle stabilization within a single platform. Beyond its catalytic efficiency in synthesizing pyrano[2,3-d]pyrimidine derivatives, the nanocomposite demonstrated cytotoxic activity in ImGIST cells.

Treatment with ZnO@CS-baicalein/Au NPs reduced viability in ImGIST cells, a patient-derived, SV40LT-immortalized gastric GIST model harboring a receptor tyrosine kinase (KIT) exon 11 V560del mutation, with a half maximal inhibitory concentration (IC₅₀) of 109 µg/mL (16,18). While this demonstrates measurable antitumor activity in a molecularly relevant KIT-mutant context, the concentration required for half-maximal inhibition remains relatively high compared with clinically established targeted agents used in GIST. Moreover, reliance on a single immortalized and imatinib-sensitive model limits assessment of broader biological relevance across the heterogeneous GIST spectrum, particularly in more refractory disease settings. Further validation in additional GIST models with diverse KIT/platelet-derived growth factor receptor alpha (PDGFRA) genotypes and resistance states, together with optimization of nanoparticle formulation, intracellular uptake efficiency, and tumor selectivity, will therefore be necessary before translational relevance can be fully established.

Mechanistically, Ye et al. reported that the nanocomposite suppressed phosphoinositide 3-kinase (PI3K)/protein kinase B(Akt)/mammalian target of rapamycin (mTOR) signaling (16), a pathway widely implicated in cancer progression and therapeutic resistance (19). They also observed increased Bax and P53 expression, decreased B-cell lymphoma 2 (Bcl2) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/STAT3 levels, and S-phase accumulation. While these changes are consistent with apoptotic and cell-cycle stress responses in a GIST cell context, they do not by themselves establish meaningful interference with KIT/PDGFRA-driven GIST biology, because the study did not directly examine whether these downstream changes were linked to suppression of KIT/PDGFRA-driven signaling. At present, these findings are therefore more appropriately interpreted as preliminary mechanistic correlates of antitumor activity in GIST cells rather than definitive evidence of GIST-specific pathway targeting. Such S-phase enrichment may reflect replication stress or deoxyribonucleic acid (DNA) synthesis arrest rather than enhanced proliferation, a distinction that warrants further mechanistic clarification.

From a clinical perspective, GISTs are predominantly driven by activating mutations in KIT or PDGFRA (20,21). While surgical resection remains the curative standard for localized disease, the treatment of advanced and high-risk GIST has evolved into a sequential, genotype-informed TKI paradigm (1,21,22). Imatinib is the standard first-line therapy, followed by sunitinib, regorafenib, and ripretinib in later lines, whereas avapritinib is particularly relevant in PDGFRA exon 18-mutant disease, especially D842V-mutant GISTs (1,2,21). Nevertheless, durable complete responses remain rare, and acquired resistance driven by secondary KIT/PDGFRA alterations and interlesional heterogeneity continues to limit long-term disease control (2,23). These persistent limitations provide a rationale for exploring alternative therapeutic strategies, including nanoplatform-based approaches. In this setting, nanoplatform-based strategies may hold conceptual value not as replacements for established TKIs, but as exploratory approaches that could complement current targeted therapy and help address refractory disease biology (24). Although ZnO@CS-baicalein/Au NPs modulate downstream PI3K/Akt/mTOR signaling (16), their interaction with KIT-driven oncogenic signaling and their potential capacity to overcome TKI resistance remain unexplored. Evaluation in resistant GIST models and investigation of combination strategies with established TKIs would substantially strengthen the translational relevance of this nanoplatform.

The conceptual strength of this study lies in the functional coupling of natural-product pharmacology with nanoengineering. By incorporating baicalein—a natural flavonoid with reported anticancer activity and PI3K/Akt-related regulatory potential (17,25)—into a ZnO-based nanoscaffold and stabilizing it with gold nanoparticles, the authors created a multifunctional hybrid system. Such integration reflects a broader trend in nanomedicine toward platforms that combine catalytic properties with biological activity (26).

Nevertheless, translational challenges remain substantial. Despite encouraging preclinical findings across various tumor types (Table 1), nanoparticle-based anticancer therapies have not consistently demonstrated clear clinical superiority in terms of efficacy or safety (27). Limitations of the enhanced permeability and retention (EPR) effect (28), tumor stromal barriers, intertumoral heterogeneity, and uncertainties in biodistribution continue to constrain therapeutic benefit. Particularly in GIST—where stromal architecture may influence drug penetration—comprehensive in vivo validation, including pharmacokinetic profiling, tumor accumulation studies, resistance modeling, and long-term safety assessment, will be indispensable.

In summary, ZnO@CS-baicalein/Au NPs represent a conceptually promising but still preliminary nanoplatform for GIST, and their broader therapeutic relevance remains to be established. While the present study provides proof-of-concept evidence of in vitro antitumor activity and mechanistic modulation, future investigations will be required to bridge the gap between experimental feasibility and clinical applicability. Rigorous biological validation and rational integration with established targeted strategies will ultimately determine whether such multifunctional ZnO-based nanocomposites can contribute meaningfully to precision cancer therapy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0179/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0179/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Blay JY, Kang YK, Nishida T, et al. Gastrointestinal stromal tumours. Nat Rev Dis Primers 2021;7:22. [Crossref] [PubMed]
2. Wang XD, Shou CH, Chen SC, et al. Targeted Therapy for Advanced Gastrointestinal Stromal Tumors: Evolution and Future Directions. Drug Des Devel Ther 2026;20:594043. [Crossref] [PubMed]
3. Dutt Y, Pandey RP, Dutt M, et al. Therapeutic applications of nanobiotechnology. J Nanobiotechnology 2023;21:148. [Crossref] [PubMed]
4. Tseriotis VS, Ampazis D, Karachrysafi S, et al. ZnO-Based Nanoparticles for Targeted Cancer Chemotherapy and the Role of Tumor Microenvironment: A Systematic Review. Int J Mol Sci 2025;26:8417. [Crossref] [PubMed]
5. Mohammed AM, Mohammed M, Oleiwi JK, et al. The anticancer, antioxidant, and antimicrobial properties of zinc oxide nanoparticles: A comprehensive review. Nano TransMed 2025;4:100097.
6. Mu S, Yang H, Wang S, et al. Zinc-based Nanomaterials in Cancer Therapy: Mechanisms, Applications, and Future Directions. Theranostics 2025;15:7841-71. [Crossref] [PubMed]
7. He G, Huang Z, Zong Y, et al. ZnO nanoparticle-educated exosomes inhibit osteosarcoma metastasis through HIF-1α/miR-1287–5p/Snail axis. Nano Today 2026;68:103008.
8. Cheng J, Wang X, Qiu L, et al. Green synthesized zinc oxide nanoparticles regulates the apoptotic expression in bone cancer cells MG-63 cells. J Photochem Photobiol B 2020;202:111644. [Crossref] [PubMed]
9. Arab-Bafrani Z, Zabihi E, Jafari SM, et al. Enhanced radiotherapy efficacy of breast cancer multi cellular tumor spheroids through in-situ fabricated chitosan-zinc oxide bio-nanocomposites as radio-sensitizing agents. Int J Pharm 2021;605:120828. [Crossref] [PubMed]
10. Sun Y, Qin L, Yang Y, et al. Zinc-Based ROS Amplifiers Trigger Cancer Chemodynamic/Ion Interference Therapy Through Self-Cascade Catalysis. Small 2024;20:e2402320. [Crossref] [PubMed]
11. Zhang J, Zhang YP, Sun Q, et al. Cancer cell membrane-camouflaged pH-responsive nanoparticles for enhancing siRNA effect and synergistic anti-tumor therapy. J Nanobiotechnology 2025;23:471. [Crossref] [PubMed]
12. Dong S, Huang Y, Yan H, et al. Ternary heterostructure-driven photoinduced electron-hole separation enhanced oxidative stress for triple-negative breast cancer therapy. J Nanobiotechnology 2024;22:240. [Crossref] [PubMed]
13. Zhou M, Liang S, Liu D, et al. Manganese-Enriched Zinc Peroxide Functional Nanoparticles for Potentiating Cancer Immunotherapy. Nano Lett 2023;23:10350-9. [Crossref] [PubMed]
14. Lu Y, Chen Y, Hou G, et al. Zinc-Iron Bimetallic Peroxides Modulate the Tumor Stromal Microenvironment and Enhance Cell Immunogenicity for Enhanced Breast Cancer Immunotherapy Therapy. ACS Nano 2024;18:10542-56. [Crossref] [PubMed]
15. Ma Y, Cao Y, Zu M, et al. Flying-Saucer-Shaped Nanoheterojunctions with Enhanced Colorectal Tumor Accumulation for Increased Oxidative Stress and Immunometabolic Regulation. Advanced Functional Materials 2024;34:2402164.
16. Ye J, Shuang Q, Wu K, et al. Decorated gold nanoparticles on baicalein/chitosan-modified zinc oxide nanoparticles for one-pot preparation of pyrano2,3-dpyrimidines and inhibiting the gastrointestinal stromal tumor progression by controlling the gene expression of the cell cycle. Int J Biol Macromol 2025;322:146612. [Crossref] [PubMed]
17. Nazemiyeh A, Mahari S, Nazemiyeh N, et al. Current status and future perspectives of drug delivery systems loaded with baicalein and baicalin in cancer therapy. Biomed Pharmacother 2025;192:118589. [Crossref] [PubMed]
18. Hu X, Su P, Liu B, et al. Characterization of a Human Gastrointestinal Stromal Tumor Cell Line Established by SV40LT-Mediated Immortalization. Int J Mol Sci 2023;24:13640. [Crossref] [PubMed]
19. He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021;6:425. [Crossref] [PubMed]
20. Dermawan JK, Rubin BP. Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine. Annu Rev Pathol 2022;17:323-44. [Crossref] [PubMed]
21. Li B, Chen H, Yang S, et al. Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers. Mol Cancer 2023;22:71. [Crossref] [PubMed]
22. Tan AD, Willemsma K, MacNeill A, et al. Tyrosine kinase inhibitors significantly improved survival outcomes in patients with metastatic gastrointestinal stromal tumour: a multi-institutional cohort study. Curr Oncol 2020;27:e276-82. [Crossref] [PubMed]
23. Abudurexiti N, Lou Y, Wu M, et al. The Mechanisms of Imatinib Resistance in Gastrointestinal Stromal Tumours: Theoretical Basis and Therapeutic Aspect. J Cell Mol Med 2025;29:e70931. [Crossref] [PubMed]
24. Gabellone S, Vanni S, Fausti V, et al. Exploring nanotechnology solutions for improved outcomes in gastrointestinal stromal tumors. Heliyon 2024;10:e40596. [Crossref] [PubMed]
25. Chen X, Chen K, Ma X, et al. Identifying the potential anti-lung cancer targets of Baicalein using a network pharmacology approach. Sci Rep 2026;16:5527. [Crossref] [PubMed]
26. Wu Q, Yao X, Duan X, et al. Nanomedicine Reimagined: Translational Strategies for Precision Tumor Theranostics. Adv Mater 2026;38:e10293. [Crossref] [PubMed]
27. Ma P, Wang G, Men K, et al. Advances in clinical application of nanoparticle-based therapy for cancer treatment: A systematic review. Nano TransMed 2024;3:100036.
28. Abdullah KM, Sharma G, Singh AP, et al. Nanomedicine in Cancer Therapeutics: Current Perspectives from Bench to Bedside. Mol Cancer 2025;24:169. [Crossref] [PubMed]