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Published on: March 31, 2021
Multifunctional nano-polymer-based targeted delivery system for CRISPR/Cas9-Mediated hepatocellular carcinoma therapy
Gui Huang1, Yan Tang2, Shenghua Zhang3
1Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Jiangsu Suzhou 215123, China; Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Jiangsu Suzhou 215000, China.
Abstract:
CRISPR/Cas9 gene-editing technology exhibits substantial therapeutic potential for hepatocellular carcinoma (HCC); however, the targeted delivery of the CRISPR/Cas9 system into tumor cells remains a critical challenge requiring urgent exploration. Methyltransferase-Like 3 (METTL3), a key methyltransferase, drives HCC proliferation via multiple mechanisms. To address this challenge, a multifunctional delivery system was developed to efficiently deliver CRISPR/Cas9 plasmids targeting METTL3 (pMETTL3) into HCC cells. The cationic PEI, which facilitated the adsorption of pMETTL3 and protected it from lysosomal degradation, served as the polymeric backbone and was modified with deoxycholic acid (DOCA) to enhance its hydrophobicity. Meanwhile, lactobionic acid (LA) was grafted onto the structure to actively target HCC cells. The resulting pMETTL3/LPD was further functionalized with pH-sensitive and cleavable polyethylene glycol (PEG), aiming to reduce toxicity and enhance prolonged circulation. Results demonstrated that the delivery system maintains stability in physiological pH environments while achieving significantly enhanced accumulation in tumor tissues. Furthermore, the efficient cellular uptake of CRISPR/Cas9 plasmids enables precise gene editing, thereby effectively disrupting METTL3 expression, inducing apoptosis, and ultimately inhibiting HCC growth. This study presents a promising therapeutic strategy targeting METTL3 for HCC treatment and further expands the application of CRISPR/Cas9 gene-editing technology in cancer therapy.
Insights
A novel delivery system efficiently targets hepatocellular carcinoma (HCC) cells using CRISPR/Cas9 gene editing to inhibit tumor growth by targeting METTL3. This approach offers a promising new strategy for HCC therapy.
Area of Science:
- Biotechnology
- Oncology
- Gene Therapy
Background:
- Hepatocellular carcinoma (HCC) poses a significant therapeutic challenge.
- Targeted delivery of CRISPR/Cas9 gene-editing systems for HCC treatment is critical.
- Methyltransferase-Like 3 (METTL3) is a key driver of HCC proliferation.
Purpose of the Study:
- To develop a multifunctional delivery system for CRISPR/Cas9 plasmids targeting METTL3 in HCC cells.
- To enhance the efficiency and specificity of gene editing in HCC.
- To explore a novel therapeutic strategy for HCC treatment.
Main Methods:
- A delivery system was constructed using cationic PEI, modified with deoxycholic acid (DOCA) for hydrophobicity and lactobionic acid (LA) for active targeting of HCC cells.
- The system was further functionalized with pH-sensitive polyethylene glycol (PEG) to reduce toxicity and prolong circulation.
- CRISPR/Cas9 plasmids targeting METTL3 (pMETTL3) were encapsulated within the delivery system (pMETTL3/LPD).
Main Results:
- The delivery system demonstrated stability at physiological pH and enhanced accumulation in tumor tissues.
- Efficient cellular uptake of pMETTL3/LPD was observed, leading to precise gene editing.
- Disruption of METTL3 expression resulted in induced apoptosis and inhibited HCC growth.
Conclusions:
- The developed multifunctional delivery system effectively targets HCC cells and delivers CRISPR/Cas9 to disrupt METTL3 expression.
- This strategy shows significant potential for inhibiting HCC growth and offers a promising therapeutic avenue.
- The study expands the application of CRISPR/Cas9 technology in cancer therapy.
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