Calcium Phosphate Nanoparticles-Based Systems for RNAi Delivery: Applications in Bone Tissue Regeneration

Abstract

Bone-related injury and disease constitute a significant global burden both socially and economically. Current treatments have many limitations and thus the development of new approaches for bone-related conditions is imperative. Gene therapy is an emerging approach for effective bone repair and regeneration, with notable interest in the use of RNA interference (RNAi) systems to regulate gene expression in the bone microenvironment. Calcium phosphate nanoparticles represent promising materials for use as non-viral vectors for gene therapy in bone tissue engineering applications due to their many favorable properties, including biocompatibility, osteoinductivity, osteoconductivity, and strong affinity for binding to nucleic acids. However, low transfection rates present a significant barrier to their clinical use. This article reviews the benefits of calcium phosphate nanoparticles for RNAi delivery and highlights the role of surface functionalization in increasing calcium phosphate nanoparticles stability, improving cellular uptake and increasing transfection efficiency. Currently, the underlying mechanistic principles relating to these systems and their interplay during in vivo bone formation is not wholly understood. Furthermore, the optimal microRNA targets for particular bone tissue regeneration applications are still unclear. Therefore, further research is required in order to achieve the optimal calcium phosphate nanoparticles-based systems for RNAi delivery for bone tissue regeneration.

Keywords: RNA interference; bone tissue engineering; calcium phosphates; gene therapy; nanoparticles; non-viral vectors; surface functionalization.

Figure 1

Pathway of microRNA, from formation in the cell nucleus thanks to RNA polymerase II, to formation of RISC complex and expression.

Figure 2

Schematic of miRNAs involved in bone homeostasis (a) and bone repair (b). The miRNAs involved in bone repair are distinguished in positive regulators (green), negative regulators (red), unclear (black).

Figure 3

The main methods for surface functionalization of CaP nanoparticles loaded with genetic material (RNAi): (A) PEG-ylation, (B) Natural polymers, (C) Liposomes, (D) Cell penetrating peptides. One example of each surface functionalization method is shown. PEG-ylation using PEG and alendronate (PEG-ALE) is shown in (A) [155], the natural polymers chitosan and dopamine (-CHI) are shown in (B) [156], the use of the liposome 1,2-Dioleoyl-sn-glycero-3-phosphate (DOPA) lipid is shown in (C) [157], and the cell penetrating peptide Arginine-Glycine-Aspartic acid (RGD) is shown in (D) [74].