Nucleus-specific RNAi nanoplatform for targeted regulation of nuclear lncRNA function and effective cancer therapy

Area of Science:

• Biomedical Engineering
• Molecular Biology
• Cancer Research

Background:

• Long noncoding RNAs (lncRNAs) are emerging therapeutic targets in cancer therapy.
• Nuclear lncRNAs are difficult to regulate in vivo due to the nuclear envelope.
• Targeting nuclear lncRNAs is crucial for effective cancer treatment.

Purpose of the Study:

• To develop a nucleus-specific RNA interference (RNAi) nanoparticle (NP) platform.
• To enable targeted regulation of nuclear lncRNA function for cancer therapy.
• To investigate the efficacy of the NP platform in liver cancer models.

Main Methods:

• Development of a novel RNAi nanoplatform using nucleus-targeting peptide amphiphile (NTPA) and a pH-responsive polymer.
• Complexation of small interfering RNA (siRNA) with the nanoplatform.
• Intravenous administration and evaluation in orthotopic and subcutaneous xenograft tumor models.

Main Results:

• The nanoplatform demonstrated significant accumulation in tumor tissues and internalization by tumor cells.
• Efficient endosomal escape and nucleus targeting via importin α/β heterodimer interaction.
• Notable suppression of nuclear lncNEAT2 expression and significant inhibition of liver cancer tumor growth.

Conclusions:

• The nucleus-specific RNAi nanoplatform is a promising tool for targeting nuclear lncRNAs in cancer therapy.
• This approach effectively suppresses oncogenic lncRNA expression and tumor progression in liver cancer.
• Further development holds potential for novel therapeutic strategies against nuclear lncRNA-driven cancers.