Revolutionizing gene editing: How RGD peptide-based lipids could be the key to effective mRNA delivery

Targeted mRNA delivery: Using RGD peptides to improve specificity and efficiency

Researchers at the University of Pennsylvania have recently investigated the potential use of RGD peptide-conjugated lipids for targeted mRNA delivery and gene editing applications. RGD peptides can bind to specific cell surface receptors that are overexpressed in many types of cancer cells. The researchers synthesized a series of RGD peptide-conjugated ionizable lipids The lipids were formulated with DOPE, cholesterol, and lipid-PEG to form lipid nanoparticles which were used to deliver mRNA in vitro and in vivo, as well as co-deliver Cas9 mRNA and sgRNA for evaluation as a platform for gene editing applications. The study found that the RGD peptide-conjugated lipids were able to efficiently deliver mRNA to specific cell types and achieve high levels of gene editing efficiency. The researchers used a luciferase reporter system to demonstrate the efficacy of the lipids in vitro, showing that they were able to deliver mRNA to HeLa cells with high specificity and efficiency. The lipids were also able to deliver mRNA encoding the CRISPR-Cas9 gene editing system and base editor BE3 to HeLa cells, resulting in efficient gene editing.

 
Advantages of RGD peptide-based lipids for targeted mRNA delivery over other methods

The use of RGD peptide-based lipids for targeted mRNA delivery has several potential advantages over other delivery methods.

1. Improved specificity: RGD peptides can selectively target cells that overexpress the corresponding cell surface receptors, which can improve the specificity of the therapy. This is particularly important for gene therapies, as off-target effects can lead to unwanted side effects and reduced efficacy. By using RGD peptides to target cells with high levels of specific surface receptors, the therapy can be delivered directly to the cells that need it, while minimizing exposure to healthy cells. This can improve the therapeutic index of gene therapies and increase their efficacy.

2. Enhanced cellular uptake: mRNA is a fragile molecule that is easily degraded by enzymes in the bloodstream and is difficult to deliver to cells. RGD peptide-based lipids can protect the mRNA from degradation and facilitate its uptake by cells. The lipids form a protective layer around the mRNA, allowing it to survive in the bloodstream for longer and increasing the chances of it being taken up by cells. In addition, the RGD peptides on the surface of the lipids can bind to specific cell surface receptors, which can enhance the uptake of the mRNA by cells.

3. Reduced immunogenicity: One of the key challenges of gene therapies is the risk of triggering an immune response in the patient. This can lead to adverse reactions and reduce the efficacy of the therapy. RGD peptide-based lipids have been shown to have low immunogenicity, which means that they are less likely to trigger an immune response in the patient. This is due to the fact that RGD peptides are naturally occurring molecules that are recognized by the body, and the lipid component of the delivery system is biocompatible and less harmful.

4. Versatile design: RGD peptide-based lipids can be designed to have different physical and chemical properties, which can be tailored for specific applications. For example, the lipid component of the delivery system can be modified to improve stability, increase circulation time, or enhance cellular uptake. The RGD peptide can also be modified to increase its affinity for specific cell surface receptors or to target different types of cells or tissues. This versatility allows for the development of lipids that can deliver mRNA to different types of cells and tissues, increasing the potential for the development of effective gene therapies.

5. Potential for combination therapies: RGD peptide-based lipids can be combined with other therapeutic agents, such as small molecules or antibodies, to enhance the therapeutic effect. For example, RGD peptide-based lipids can be used to deliver mRNA encoding a therapeutic protein, while an antibody can be used to enhance the specificity of the therapy. This approach has the potential to improve the efficacy of gene therapies and address the challenges of treating complex genetic disorders.

Conclusion

Overall, RGD peptide-based lipids represent a promising approach for targeted mRNA delivery and gene editing. As our understanding of the mechanisms of gene regulation and gene therapy advances, we can expect to see continued progress in this field. The use of targeted ligands, such as RGD peptides, has the potential to improve the specificity and efficiency of gene therapies and facilitate the development of new treatments for a variety of genetic disorders. The findings of this study provide a roadmap for future research in this area and demonstrate the potential of targeting technology to transform the field of gene therapy.

As innovation occurs in delivery formulations, Avanti is the perfect partner to supply the lipids to make your project a success – including RGD-conjugated lipids! Our team of formulation and lipid synthesis experts are here to innovate with you and tackle challenges head on.

https://pubs.rsc.org/en/content/articlelanding/2022/ra/d2ra02771b