Targeted delivery of circPDHK1 siRNA via aptamer functionalized lipid nanoparticles inhibits ccRCC growth and migration

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.