Adv. Sci.: A built-in aptamer reservoir with nuclease-resistant 3D cascade assembled DNA nanoclusters for precision cancer treatment

Innovation: Wu Regener's team at Fuzhou University has developed aptamer embedded 3D DNA nanoclusters (Apt-eNC) as intelligent carriers
for cancer targeted drug delivery.
Apt-eNC is designed to have a built-in reserve pool in the inner cavity where the aptamer can move
outward.
When surface aptamers are degraded, the aptamers in the reserve pool can move outward to provide compensation, thereby maintaining their continuous tumor-targeting performance in vivo, providing new ideas
for precision cancer treatment.

Keywords: 3D layered DNA nanoclusters, built-in aptamer reservoir, cancer precision treatment, outward movement

Chemotherapy drugs have been widely used in the treatment
of various cancers as the main anti-cancer drugs.
However, standard chemotherapy drugs lack tumor targeting capabilities and are often distributed non-specifically throughout the body through the systemic circulation, inevitably leading to severe damage
to healthy tissues and organs.
In order to alleviate systemic toxicity, traditional anti-cancer drugs need to reduce the dose of the drug to a level lower than normal cells can tolerate, without side effects on normal cells, directly leading to insufficient dose in the tumor area, thereby affecting its inherent therapeutic effect
.
Therefore, there is an urgent need to develop a specific tumor-targeted drug delivery system
for cancer chemotherapy.
As a natural biological macromolecule, DNA has the characteristics of high water solubility, good biocompatibility, modifiability and drug loading, and is a potential raw material for the construction of DNA drug carriers.
Functional nucleic acids (aptamers) have cell-targeting capabilities comparable to antibodies, but they are easily degraded
.
Although chemical modification can enhance the stability of aptamers, chemical modifications often weaken or lose aptamer recognition, and bring additional toxic side effects
.
Safety hazards and insufficient efficacy of chemotherapy have become the two main limitations of
DNA nanostructured drug carriers failing in clinical trials.
Considering that rigid and dense DNA nanostructures have strong resistance to nuclease degradation, can prolong blood circulation time, and have enough time to search for and gather at cancerous sites, it is urgent and urgent to develop a multifunctional drug delivery vector with high biocompatibility, high drug load, good anti-degradation ability, and can prevent accidental drug leakage and enhance tumor accumulation in vivo
.

The Wu Regeng team of Fuzhou University discussed the above problems: a 3D DNA nanocluster structure (Apt-eNC) embedded by aptamers was constructed as an intelligent carrier for cancer targeted drug delivery, and Apt-eNC composites loaded with anti-cancer drugs were used to achieve precise treatment
of cancer.
The results were published in
Advanced Science.

Based on unique structural features, Apt-eNC has shown obvious advantages
in targeted drug delivery.
(a) Long
circulation time in the body.
sgc8-eNC can maintain its structural integrity in serum solution or in vivo environment for 8 hours
.
(b) Extremely high cargo loading capacity
.
Sgc8-eNC consists of 283 Tetra units with enough binding sites to accommodate a large number of therapeutic agents, making the drug-to-carrier ratio as high as 5670:1, and the drug-loaded material can remain stable under physiological pH to prevent early leakage
.
(c) Sustained tumor targeting in a complex environment
.
Drug-loaded Apt-eNC can specifically identify PTK7-positive tumor cells and specifically internalize into tumor tissues
through receptor-guided endocytosis.
In addition, it can maintain the targeted activity of tumor tissue during blood circulation, reducing off-target toxic side effects
that are harmful to healthy tissues of the delivered drug.
(d) Good biocompatibility
.
Even with very high concentrations of DNA components, Apt-eNC is not significantly toxic
at the cellular level.
After intensive loading of chemotherapy drugs, there were no significant cytotoxicity or adverse reactions
to healthy tissues and normal organs at the systemic level.
(e) Good versatility
due to significant sequence programmability.
(f) The material construction procedure is simple and the assembly efficiency is high
.
It is worth noting that the experimental data from nuclease degradation resistance, payload capacity and molecular mechanisms of targeting tumors in vivo, especially the therapeutic effect of targeted delivery of drugs to tumor tissues and tumor tissues through in vivo circulation, show that Apt-eNC is a drug delivery system
with precise targeting capabilities 。 More importantly, the specific birigid structure and the ingenious design of the built-in aptamer reserve pool provide important new technical references for the design of complex DNA structures, such as the anti-degradation ability of nucleases with enhanced mechanical stiffness and the spatial displacement effect of automatically adjusting recognition elements, which provides new ideas
for maintaining the targeted activity of drug carriers, sufficient delivery, and finally meeting the requirements of professional applications in the biomedical field.

WILEY

Paper Information:

Outward Movement of Targeting Ligands from a Built-In Reserve Pool in Nuclease-Resistant 3D Hierarchical DNA Nanocluster for in Vivo High-Precision Cancer Therapy

Weijun Wang, Yansha Gao, Yaxin Chen, Wenqing Wang, Qian Li, Zhiyi Huang, Jingjing Zhang, Qi Xiang, and Zai-Sheng Wu

Advanced Science

DOI: 10.
1002/advs.
202203698

Click "Read Original" in the lower left corner to view the original paper
.

Advanced

Science

Introduction to the journal