RGD peptide-based lipids for targeted mRNA delivery and gene editing applications

Abstract

We developed RGD peptide based ionizable lipids, which can be formulated into LNPs for integrin-dependent targeted mRNA delivery and gene editing applications.

Investigation of enhanced intracellular delivery of nanomaterials modified with novel cell-penetrating zwitterionic peptide-lipid derivatives

“…In the evaluation of physicochemical properties, modification of GG-(EK) 4 -lipid and KK-(EK) 4 -lipid did not affect the particle size of mRNA-LNPs but increased the PDI ( Table 4 ). On the other hand, KK-(EK) 4 /mRNA-LNPs and GG-(EK) 4 /mRNA-LNPs showed encapsulation efficiencies comparable to those of unmodified mRNA-LNPs, and these encapsulation efficiencies were consistent with a previous report on the modification of peptide-modified lipids into mRNA-LNPs by self-assembly using a microfluidic device (Qin et al., 2022 ). In addition, in the evaluation of luciferase expression in A549 cells, KK-(EK) 4 /mRNA-LNPs showed higher expression than unmodified mRNA-LNPs and GG-(EK) 4 /mRNA-LNPs ( Figure 7 ).…”

RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions

“…The choice of delivery system can have a significant impact on the immunogenicity of RGD peptides, which may include liposomes, nanoparticles, and micelles, etc. It is needed to find the most suitable option for reducing immunogenicity while maintaining therapeutic efficacy 96–99 . Considering the diversity of major histocompatibility complex (MHC) alleles in different populations and races, designing personalized peptides based on an individual's MHC profile can help reduce the risk of immunogenicity 100 .…”

Development of polypeptide-based materials toward messenger RNA delivery

“…Strategies such as surface PEGylation or decoration with polyanions can typically enhance passive targeting, thereby improving the serum stability and extending the blood circulation of gene vectors. 76 On the other hand, the active targeting strategy for mRNA delivery is to use targeting molecules, such as antibody, mannose, Arg-Gly-Asp peptide (RGD), 77 Cys-Lys-Lys-Lys (CKKK), 78 which specifically bind to receptors that are overexpressed on the surface of target cells, enhancing the uptake of the mRNA delivery system by those cells. For example, Dong et al demonstrated RGD modified mRNA nanocomplexes exhibited prolonged blood circulation and yielded much higher mRNA expression in tumours via intravenous administration compared to non-cRGD nanoformulation.…”

“…Ionizable lipids, exemplified by their success in clinically approved lipid nanoparticle formulations, offer pH responsiveness, efficient endosomal escape, and a mimicry of natural cellular membranes. 3,77 On the other hand, polypeptides show advantages such as stimuli responsiveness, biodegradability, and a high degree of customization, making them valuable for applications that demand tailored and targeted nucleic acid delivery with a focus on adaptability to diverse biological environments. 10,34 Further investigation is needed to develop principles and strategies for the rational design of targeted mRNA polymeric carriers that can effectively target specific cells, tissues, and organs.…”