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Site-targeted drug delivery systems enhance therapeutic efficacy while minimizing systemic toxicity and treatment costs. Unlike conventional methods, these systems ensure precise drug delivery, improving bioavailability and reducing side effects. Targeted drug delivery is classified into three levels. First-order targeting directs drugs to the capillary beds of specific organs or tissues. Second-order targets specific cell types, such as tumor cells, using receptor-mediated interactions.
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Updated: May 13, 2026

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
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DNA-Based nanostructures for tumor microenvironment-responsive drug delivery.

Siqi Li1, Mengdi Xu2, Chi Yao2

  • 1State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, P.R. China; Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, College of Chemistry and Materials, Fudan University, Shanghai, 200438, P.R. China.

Advanced Drug Delivery Reviews
|May 26, 2025
PubMed
Summary

DNA nanostructures offer precise control for targeted drug delivery, responding to the unique tumor microenvironment (TME). This review explores TME-responsive DNA nanostructures for advanced cancer therapeutics.

Keywords:
DNA nanotechnologyDrug deliveryStimuli-responsivenessTumor microenvironment

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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Drug Delivery

Background:

  • DNA nanostructures possess sequence programmability, biocompatibility, and structural versatility, making them suitable for biomedical applications.
  • The tumor microenvironment (TME) presents challenges for conventional therapies due to its unique characteristics like pH gradients, high glutathione (GSH), hypoxia, and abundant adenosine triphosphate (ATP).
  • DNA nanostructures enable precise control over drug loading, tumor targeting, and spatiotemporal release, ideal for overcoming TME challenges in drug delivery.

Purpose of the Study:

  • To review recent advances in versatile TME-responsive DNA-based nanostructures for precise therapeutic drug delivery.
  • To discuss design principles for DNA nanostructures in TME-responsive drug delivery.
  • To summarize TME characteristics that regulate targeting and controlled release from DNA nanostructures.

Main Methods:

  • Review of recent literature on DNA nanostructures and TME-responsive drug delivery.
  • Analysis of design principles for structural configuration and functional integration.
  • Summary of mechanisms by which TME stimuli (pH, GSH, ATP, enzymes, multiple) regulate drug release.

Main Results:

  • DNA nanostructures can be engineered to respond to specific TME stimuli for targeted drug delivery.
  • TME characteristics can be leveraged to trigger drug release from DNA nanostructures with high specificity.
  • Versatile DNA nanostructures offer precise control over therapeutic payload delivery in the tumor microenvironment.

Conclusions:

  • TME-responsive DNA nanostructures represent a promising platform for next-generation cancer therapeutics.
  • Optimizing DNA nanostructure design requires interdisciplinary collaboration for smart, precise, safe, and potent drug delivery.
  • Future research should focus on enhancing the designability and therapeutic capabilities of DNA nanostructure-based drug delivery systems.