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Programmable Tetrahedral DNA-RNA Nanocages Woven with Stimuli-Responsive siRNA for Enhancing Therapeutic Efficacy of
Changmai Chen1, Maocheng Yu1, Qing Li1
1Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China.
Abstract:
Multidrug resistance (MDR) is a major obstacle limiting the effectiveness of chemotherapy against cancer. The combination strategy of chemotherapeutic agents and siRNA targeting drug efflux has emerged as an effective cancer treatment to overcome MDR. Herein, stimuli-responsive programmable tetrahedral DNA-RNA nanocages (TDRN) have been rationally designed and developed for dynamic co-delivery of the chemotherapeutic drug doxorubicin and P-glycoprotein (P-gp) siRNA. Specifically, the sense and antisense strand sequences of the P-gp siRNA, which are programmable bricks with terminal disulfide bond conjugation, are precisely embedded in one edge of the DNA tetrahedron. TDRN provides a stimuli-responsive release element for dynamic control of functional cargo P-gp siRNA that is significantly more stable than the "tail-like" TDN nanostructures. The stable and highly rigid 3D nanostructure of the siRNA-organized TDRN nanocages demonstrated a notable improvement in the stability of RNase A and mouse serum, as well as long-term storage stability for up to 4 weeks, as evidenced by this study. These biocompatible and multifunctional TDRN nanocarriers with gold nanocluster-assisted delivery (TDRN@Dox@AuNCp) are successfully used to achieve synergistic RNAi/Chemo-therapy in vitro and in vivo. This programmable TDRN drug delivery system, which integrates RNAi therapy and chemotherapy, offers a promising approach for treating multidrug-resistant tumors.
Insights
This study introduces novel DNA-RNA nanocages for co-delivering chemotherapy and siRNA to combat multidrug resistance in cancer. These stable nanocarriers offer a promising synergistic treatment approach.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapy
Background:
- Multidrug resistance (MDR) significantly hinders chemotherapy efficacy.
- Combining chemotherapy with RNA interference (RNAi) targeting drug efflux mechanisms is a strategy to overcome MDR.
Purpose of the Study:
- To design and develop stimuli-responsive DNA-RNA nanocages (TDRN) for co-delivery of doxorubicin and P-glycoprotein (P-gp) siRNA.
- To enhance the stability and efficacy of siRNA delivery for cancer treatment.
Main Methods:
- Programmable tetrahedral DNA-RNA nanocages (TDRN) were synthesized with embedded P-gp siRNA.
- The TDRN system was designed for stimuli-responsive cargo release.
- Nanocage stability against RNase A, mouse serum, and long-term storage was evaluated.
- Co-delivery efficacy was assessed in vitro and in vivo using doxorubicin and gold nanoclusters (AuNCp).
Main Results:
- The TDRN nanostructures demonstrated enhanced stability compared to existing nanostructures.
- Significant improvements in stability against enzymatic degradation and serum were observed.
- Long-term storage stability of up to 4 weeks was achieved.
- Successful synergistic RNAi and chemotherapy (TDRN@Dox@AuNCp) was demonstrated in vitro and in vivo.
Conclusions:
- Stimuli-responsive TDRN nanocarriers provide a stable and effective platform for co-delivering chemotherapy drugs and siRNA.
- This programmable nanodelivery system offers a promising strategy for treating multidrug-resistant cancers.
- The integration of RNAi and chemotherapy presents a potent approach for enhanced cancer treatment.
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