Targeted delivery of circPDHK1 siRNA via aptamer functionalized lipid nanoparticles inhibits ccRCC growth and
Hao Ning1, Yan Jiang1, Binbin Li1
1College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China.
Abstract:
Clear Cell Renal Cell Carcinoma (ccRCC) is a common malignancy with high mortality in China, requiring innovative treatments. Recent advances in nucleic acid drugs, notably small interfering RNAs (siRNAs), show promise for therapeutic applications. Circular RNAs (circRNAs) play vital roles in cancer progression, and our previous work has identified that upregulated circPDHK1 can promote ccRCC growth and migration. However, the delivery strategies of si circPDHK1 targeting the circPDHK1 against ccRCC are not thoroughly investigated. Here, we developed a novel nucleic acid drug delivery system, AS1411/LNP-si circPDHK1, utilizing lipid nanoparticles (LNPs) encapsulated with siRNA targeting circPDHK1 and modified with the AS1411 aptamer for precise tumor targeting. In vitro and in vivo studies demonstrated that AS1411/LNP-si circPDHK1 efficiently delivered si circPDHK1 to ccRCC cells, resulting in a significant reduction in circPDHK1 expression. This delivery system exhibited superior tumor-targeting capabilities and prolonged circulation time compared with non-targeted formulations. Notably, AS1411/LNP-si circPDHK1 successfully inhibited the phosphorylation of the mTOR-AKT pathway, suppressed the proliferation and migration of ccRCC cells, and exhibited minimal side effects in vital organs. Taken together, the aptamer-guided LNP loaded siRNA targeting circPDHK1 (AS1411/LNP-si circPDHK1) displays great potential for ccRCC therapy.
Insights
A novel aptamer-guided lipid nanoparticle system effectively delivers siRNA targeting circPDHK1 to clear cell renal cell carcinoma (ccRCC). This targeted therapy inhibits tumor growth and migration, showing promise for ccRCC treatment.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Clear Cell Renal Cell Carcinoma (ccRCC) presents a significant health challenge, necessitating advanced therapeutic strategies.
- Circular RNAs (circRNAs), specifically circPDHK1, are implicated in ccRCC progression, driving tumor growth and metastasis.
- Effective delivery of small interfering RNAs (siRNAs) targeting circRNAs remains a hurdle in ccRCC treatment.
Purpose of the Study:
- To develop and evaluate a novel targeted nucleic acid drug delivery system for ccRCC therapy.
- To investigate the efficacy of AS1411/LNP-si circPDHK1 in delivering siRNA against circPDHK1 to ccRCC cells.
- To assess the therapeutic potential of this system in inhibiting ccRCC progression both in vitro and in vivo.
Main Methods:
- Development of AS1411 aptamer-conjugated lipid nanoparticles (LNPs) encapsulating siRNA targeting circPDHK1.
- In vitro assessment of cellular uptake, circPDHK1 knockdown efficiency, and impact on ccRCC cell proliferation and migration.
- In vivo evaluation of tumor targeting, pharmacokinetic profile, therapeutic efficacy, and safety in ccRCC models.
Main Results:
- AS1411/LNP-si circPDHK1 demonstrated efficient delivery of si circPDHK1 to ccRCC cells, significantly reducing circPDHK1 expression.
- The targeted delivery system exhibited enhanced tumor accumulation and prolonged circulation compared to non-targeted formulations.
- Treatment suppressed ccRCC cell proliferation and migration by inhibiting the mTOR-AKT pathway, with minimal observed toxicity in vital organs.
Conclusions:
- The aptamer-guided LNP delivery system (AS1411/LNP-si circPDHK1) is a promising strategy for targeted ccRCC therapy.
- This novel system effectively targets ccRCC, reduces circPDHK1 expression, and inhibits tumor progression.
- AS1411/LNP-si circPDHK1 holds potential for clinical application in treating clear cell renal cell carcinoma.
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