The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Transcytosis-Triggering Nanoparticles for Overcoming Stromal Barriers and Reversing Immunosuppression in Pancreatic Cancer Combinatorial Therapy
Abstract
In pancreatic ductal adenocarcinoma (PDAC), stromal cells and matrix proteins form a dense physical barrier that, while preventing the outward spread of tumor cells, also limits the penetration of drugs and CD8 + T cells inward. Additionally, the overactivated TGF-β/SMAD signaling pathway further promotes matrix proliferation and immune suppression. Therefore, crossing the stromal barrier while preserving the integrity of the stroma, releasing drugs intratumorally, remodeling the stroma, and activating the immune system is a promising drug delivery strategy. In this work, a type of enamine N -oxides modified nanoparticle was prepared, with stearic acid-modified gemcitabine prodrug (GemC18) and p SMAD2/3 inhibitor galunisertib encapsulated. The peripheral enamine N -oxides can trigger transcytosis and then respond to hypoxia and acidic microenvironments, turning the surface charge of the nanoparticles to a positive charge and enhancing penetration. The released galunisertib inhibits the TGF-β/SMAD signaling pathway, reshapes the matrix, activates antitumor immunity, and combines with gemcitabine (Gem) to kill tumor cells.
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In the citing paper
“hypoxia-reduced charge-switch micelles achieve transport beyond 400 μm in desmoplastic pancreatic tumor tissue sections and reprogram TGF-β/SMAD stroma [105]”
From Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration (2026) · cites this paper as [105]
In the citing paper
“Perivascular transport distance 407.5 ± 41.2 µm”
From Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration (2026) · cites this paper as [105]
In the citing paper
“Modeling indicates that sub-50 nm dimensions favor diffusion, whereas interstitial fluid retention elevates IFP and shapes uptake fields, underscoring the need to co-optimize particle physics with tumor hydraulics [105, 108, 115].”
From Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration (2026) · cites this paper as [105]
In the citing paper
“Hypoxia-reduced charge-switch micelles that trigger transcytosis | Hypoxia and low pH | N-oxide based micelles with CBP decoration; gemcitabine derivative and galunisertib | Stealth during circulation; reduction to tertiary amines switches charge; activation of transcytosis; TGF-β/SMAD stroma remodeling”
From Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration (2026) · cites this paper as [105]
In the citing paper
“Hypoxia-reduced charge-switch micelles that concurrently trigger transcytosis and stromal remodeling stand out for depth of transport, reaching beyond 400 µm in dense pancreatic tumors and providing robust chemo-immunotherapy synergy, but they also exemplify the highest level of formulation complexity.”
From Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration (2026) · cites this paper as [105]
Citations
Cites
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590
The entry of nanoparticles into solid tumours
Sindhwani, S., Syed, A. M., Ngai, J., Kingston, B. R., Maiorino, L., Rothschild, J., MacMillan, P., Zhang, Y., Rajesh, N. U., Hoang, T., et al. (2020) · Nature Materials · doi:10.1038/s41563-019-0566-2 · Cited by 1,732
Pancreatic cancer stroma: an update on therapeutic targeting strategies
Hosein, A. N., Brekken, R. A., & Maitra, A. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0300-1 · Cited by 950
Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges
Martin, J. D., Seano, G., & Jain, R. K. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114700 · Cited by 530
Remodeling of imbalanced extracellular matrix homeostasis for reversal of pancreatic fibrosis
Qi, L., Han, H., Han, M.-M., Sun, Y., Xing, L., Jiang, H.-L., Pandol, S. J., & Li, L. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2022.121945 · Cited by 36
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Cited by
Sorted by citations
Sheng, J., Yuan, W., Zhang, M., Chen, Z., Qi, Y., Zhao, Y., & Zhang, S. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04028-7 · Cited by 35
Self-citation
Metadata
- Authors
- Zhang, S., You, H., Fan, H., Chen, Y., Song, H., Zhao, Z., Chen, Q., Wang, Y., Tian, Z., Wu, Y., Zhou, Z., Guo, Y., Su, B., Li, X., Jia, R., Fang, M., Jiang, C., & Sun, T.
- Venue
- Nano Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2025-02-06
- Volume
- 25
- Issue
- 7
- Pages
- 2949-2959
- ISSN
- 1530-6984
- 1530-6992
- Cited by
- 34
- References
- 5
- Language
- en
- Licence
- Funders
- Natural Science Foundation of Shanghai Municipality (22ZR1414100)
- National Natural Science Foundation of China (82361148716, 82473853)
- Science and Technology Innovation Plan Of Shanghai Science and Technology Commission (2018SHZDZX01, 24430710700)
- ZJLab
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