Surfaces, Interfaces, and Applications
- Rong Wang
Rong Wang
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
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- Ke Wang
Ke Wang
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
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- Zhuolin Li
Zhuolin Li
Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
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- Haoping Long
Haoping Long
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
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- Dongyu Zhang
Dongyu Zhang
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
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- Yanting Li
Yanting Li
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
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- Zhuolu Xia
Zhuolu Xia
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
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Xindong Guo
Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
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- Wei Chen*
Wei Chen
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
*Email: [emailprotected]
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- Feng Cao*
Feng Cao
Department of Pharmaceutical, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China
*Email: [emailprotected]
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- Feng Jiang*
Feng Jiang
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China
*Email: [emailprotected]
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ACS Applied Materials & Interfaces
Cite this: ACS Appl. Mater. Interfaces 2025, XXXX, XXX, XXX-XXX
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https://pubs.acs.org/doi/10.1021/acsami.5c02384
Published April 27, 2025
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Abstract
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Gemcitabine (GTB), a clinically approved nucleoside analogue for cancer treatment, faces therapeutic limitations due to rapid enzymatic deactivation by cytidine deaminase (CDA) in tumor microenvironments. Over 90% of systemically administered GTB undergoes catalytic conversion to inactive 2′-deoxy-2′,2′-difluorouracil metabolites through CDA-mediated deamination. To address this pharmacological challenge, we developed a multifunctional codelivery nanosystem through strategic engineering of reactive oxygen species (ROS)-generating, mitochondria-targeting CPUL1-TPP (CT) nanoaggregates. These self-assembling CT/GTB complexes were further optimized with DSPE-MPEG2k (DP) and Angiopep-2-conjugated DSPE-MPEG2k (Ang-DP) to create blood–brain barrier (BBB)-penetrating Ang-DP@CT/GTB nanoparticles, enhancing both physiological stability and low-density lipoprotein receptor-related protein 1 (LRP1)-mediated glioma targeting. Comparative analyses revealed that Ang-DP@CT/GTB nanoparticles significantly enhanced GTB’s antiglioblastoma efficacy compared to free drug administration in both in vitro and in vivo models. Mechanistic investigations demonstrated that the nanosystem upregulates heme oxygenase-1 (HO-1), subsequently downregulating CDA expression to mitigate GTB metabolism. This coordinated molecular modulation prolongs GTB’s therapeutic activity while leveraging the ROS-generating capacity of CT components for synergistic tumor suppression. The BBB-permeable codelivery platform exemplifies a rational design paradigm for multifunctional carrier-free pure nanodrugs (PNDs), demonstrating how clinical drug reformulation can overcome inherent pharmacokinetic limitations. This nanotechnology-driven approach provides critical insights for optimizing chemotherapeutic performance through metabolic pathway regulation and targeted delivery engineering.
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© 2025 American Chemical Society
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- Cancer
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- Fluorescence
- Rodent models
- Tumors
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ACS Applied Materials & Interfaces
Cite this: ACS Appl. Mater. Interfaces 2025, XXXX, XXX, XXX-XXX
Click to copy citationCitation copied!
Published April 27, 2025
Publication History
Received
Accepted
Revised
Published
online
© 2025 American Chemical Society
Request reuse permissions
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