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Core-Shell Nanosystems for Self-Activated Drug-Gene Combinations against Triple-Negative Breast Cancer
Peng Liu1, Xuanjun Liu1, Yan Cheng1
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
Abstract:
The combination of gene therapy with chemotherapeutics provides an efficacious strategy for enhanced tumor therapy. RNA-cleaving DNAzyme has been recognized as a promising gene-silencing tool, while its combination with chemotherapeutic drugs has been limited by the lack of an effective codelivery system to allow sufficient intracellular DNAzyme activation, which requires specific metal ions as a cofactor. Here, a self-activatable DNAzyme/drug core-shell codelivery system is fabricated to combat triple-negative breast cancer (TNBC). The hydrophobic chemotherapeutic, rapamycin (RAP), is self-assembled into the pure drug nanocore, and the metal-organic framework (MOF) shell based on coordination between Mn2+ and tannic acid (TA) is coated on the surface to coload an autophagy-inhibiting DNAzyme. The nanosystem efficiently delivers the payloads into tumor cells, and upon endocytosis, the MOF shell is disintegrated to release the therapeutics in response to an acidic endo/lysosome environment and intracellular glutathione (GSH). Notably, the coreleased Mn2+ serves as the cofactor of DNAzyme for effective self-activation, which suppresses the expression of Beclin 1 protein, the key initiator of autophagy, resulting in a significantly strengthened antitumor effect of RAP. Using tumor-bearing mouse models, the nanosystem could passively accumulate into the tumor tissue, impose potent gene-silencing efficacy, and thus sensitize chemotherapy to inhibit tumor growth upon intravenous administration, providing opportunities for combined gene-drug TNBC therapy.
Insights
A novel nanodelivery system combines gene therapy with chemotherapy to treat triple-negative breast cancer (TNBC). This system effectively delivers DNAzyme and rapamycin, enhancing cancer cell death and inhibiting tumor growth.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Gene therapy and chemotherapy offer synergistic potential for improved tumor treatment.
- RNA-cleaving DNAzymes are effective gene-silencing agents, but their therapeutic use is hindered by challenges in codelivery and activation.
- Triple-negative breast cancer (TNBC) remains a significant therapeutic challenge requiring innovative treatment strategies.
Purpose of the Study:
- To develop a self-activatable DNAzyme/drug core-shell nanodelivery system for enhanced TNBC therapy.
- To investigate the codelivery of an autophagy-inhibiting DNAzyme and rapamycin for synergistic antitumor effects.
- To evaluate the efficacy of the nanosystem in preclinical TNBC models.
Main Methods:
- Fabrication of a core-shell nanocarrier with a rapamycin (RAP) nanocore and a metal-organic framework (MOF) shell.
- The MOF shell, composed of Mn2+ and tannic acid (TA), co-loaded an autophagy-inhibiting DNAzyme.
- In vitro and in vivo evaluation of payload release, cellular uptake, gene silencing, autophagy inhibition, and antitumor efficacy in TNBC models.
Main Results:
- The nanosystem successfully delivered both rapamycin and DNAzyme into tumor cells.
- The MOF shell degraded in response to acidic and reductive intracellular environments, releasing Mn2+ for DNAzyme self-activation.
- Activated DNAzyme suppressed Beclin 1 expression, inhibiting autophagy and potentiating the chemotherapeutic effect of rapamycin, leading to significant tumor growth inhibition in vivo.
Conclusions:
- The developed self-activatable DNAzyme/drug nanodelivery system provides an effective platform for combined gene-drug therapy against TNBC.
- The system demonstrates efficient payload codelivery, stimuli-responsive release, and synergistic therapeutic outcomes by inhibiting autophagy and enhancing chemotherapy.
- This approach offers a promising strategy for advancing TNBC treatment through integrated gene and drug delivery.
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