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Antisense Oligonucleotide Embedded Context Responsive Nanoparticles Derived from Synthetic Ionizable Lipids for
Sourav Sarkar1, Parikshit Moitra2, Sayan Bera1
1School of Applied & Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India.
Abstract:
The long noncoding RNAs (lncRNA) are primarily associated with several essential gene regulations but are also connected to cancer metabolism and progression. HOTAIR and MALAT1 are two such lncRNAs that are detected in malignancies of various origins and are responsible for the poor prognosis of cancer patients. Due to these factors, the lncRNAs have emerged as prime targets for the development of anticancer therapeutics. However, nonviral delivery of lncRNA-targeted antisense oligonucleotides (ASOs) still remains a critical challenge while maintaining their structural and functional integrity. Herein, we have designed and synthesized a new series of ionizable lipids with variations in their head groups to prepare lipid nanoparticle (LNP) formulation along with cholesterol-based twin cationic lipid and amphiphilic zwitterionic lipid. The context responsiveness of these formulations in delivering the ASOs has been thoroughly investigated by various bioanalytical techniques, and an optimum formulation has been identified. The LNPs are utilized to deliver the ASOs targeting HOTAIR lncRNA in human cancer cell lines and MALAT1 lncRNA in mouse models. This study thus standardizes an advanced nanomaterial system for nonviral gene delivery that has been validated by a considerable reduction in the target lncRNA level under in vitro and a significant reduction in tumor volume under in vivo settings.
Insights
Researchers developed novel lipid nanoparticles (LNPs) for nonviral delivery of antisense oligonucleotides (ASOs) targeting cancer-promoting long noncoding RNAs (lncRNAs). This advanced system effectively reduces lncRNA levels and tumor volume, offering a promising cancer therapy approach.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Nanotechnology
Background:
- Long noncoding RNAs (lncRNAs), including HOTAIR and MALAT1, are implicated in cancer progression and poor patient prognosis.
- Targeting lncRNAs with antisense oligonucleotides (ASOs) presents a therapeutic strategy, but efficient nonviral delivery remains a significant challenge.
- Maintaining the structural and functional integrity of ASOs during delivery is crucial for therapeutic efficacy.
Purpose of the Study:
- To design and synthesize novel ionizable lipids for advanced lipid nanoparticle (LNP) formulations.
- To develop a context-responsive LNP system for efficient nonviral delivery of lncRNA-targeting ASOs.
- To evaluate the efficacy of LNP-mediated ASO delivery against HOTAIR and MALAT1 lncRNAs in vitro and in vivo.
Main Methods:
- Synthesis of novel ionizable lipids with varied head groups, formulated into LNPs with cholesterol-based twin cationic lipid and amphiphilic zwitterionic lipid.
- Investigation of LNP formulation context-responsiveness using bioanalytical techniques to identify an optimal formulation.
- In vitro delivery of ASOs targeting HOTAIR lncRNA in human cancer cell lines and in vivo delivery of ASOs targeting MALAT1 lncRNA in mouse models.
Main Results:
- An optimized LNP formulation was identified for efficient and context-responsive delivery of ASOs.
- Significant reduction in target lncRNA levels (HOTAIR and MALAT1) was observed under in vitro conditions.
- Substantial reduction in tumor volume was achieved in vivo, demonstrating therapeutic potential.
Conclusions:
- A novel nanomaterial system for nonviral gene delivery using optimized LNPs has been successfully developed and validated.
- The developed LNP system effectively delivers ASOs to reduce oncogenic lncRNA expression and inhibit tumor growth.
- This study provides a standardized and advanced platform for lncRNA-targeted cancer therapy.
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