Delivery of RNAi-Based Therapeutics for Bone Regeneration

Abstract

Purpose of review: The clinical significance, target pathways, recent successes, and challenges that preclude translation of RNAi bone regenerative approaches are overviewed.

Recent findings: RNA interference (RNAi) is a promising new therapeutic approach for bone regeneration by stimulating or inhibiting critical signaling pathways. However, RNAi suffers from significant delivery challenges. These challenges include avoiding nuclease degradation, achieving bone tissue targeting, and reaching the cytoplasm for mRNA inhibition. Many drug delivery systems have overcome stability and intracellular localization challenges but suffer from protein adsorption that results in clearance of up to 99% of injected dosages, thus severely limiting drug delivery efficacy. While RNAi has myriad promising attributes for use in bone regenerative applications, delivery challenges continue to plague translation. Thus, a focus on drug delivery system development is critical to provide greater delivery efficiency and bone targeting to reap the promise of RNAi.

Keywords: Bone regeneration; Drug delivery systems; RNAi; miRNA; siRNA.

Figure 1.

A spatiotemporal cascade of multiple endogenous factors controls normal bone regeneration during fracture repair in four stages. PDGF = platelet derived growth factor; VEGF = vascular endothelial growth factor; FGF = fibroblast growth factor; TNF = tumor necrosis factor; SDF = stromal cell-derived factor; IGF = insulin-like growth factor; BMP = bone morphogenetic protein; OPG = osteoprotegerin; IL = interleukin; TGF = transforming growth factor; Ang = angiopoietin; M-CSF = macrophage colony stimulating factor; RANK = receptor activator of nuclear factor κB; RANKL = RANK-ligand. Reproduced from [4] with permission.

Figure 2.

Osteoblasts, osteoclasts, osteoprogenitors, osteocytes, and monocytes communicate through direct interactions and paracrine effects. RANKL = receptor activator of nuclear factor kappa B (RANK) ligand; OPG = osteoprotegerin; M-CSF = macrophage colony stimulating factor; BMP = bone morphogenetic protein; IGF = insulin-like growth factor; CTHRC1 = collagen triple helix repeat containing 1; TRAP = tartrate-resistant acid phosphatase; Cx43 = connexin 43; Wnt = wingless-related integration site; Ror = receptor tyrosine kinase-like orphan receptor; Fzd = frizzled; TRIP = transforming growth factor beta receptor (TGFβR)-interacting protein; S1P = sphingosine 1-phosphate; S1P₁ = S1P receptor.

Figure 3.

Schematic of fracture healing, highlighting the various cells and factors that are negative and positive regulators of regeneration and highlighting potential targets for siRNA interventions. Abbreviations: ACP5 = acid phosphatase 5; ALPL = alkaline phosphatase; ANG = angiopoietin; BGLAP = bone gamma-carboxyglutamate protein (Osteocalcin); BMP = bone morphogenetic proteins; COL1A1 collagen type I, alpha 1; DKK1 = dickkopf-related protein 1; IL = interleukin; M-CSF = macrophage colony-stimulating factor; MSC = mesenchymal stem cell; OPG = osteoprotegerin; PPARG = peroxisome proliferator-activated receptor gamma; PTH = parathyroid hormone; RANKL = receptor activator of nuclear factor kappa-B ligand; RUNX2 = runt-related transcription factor 2; SOX-9 = sex determining region Y-Box 9; SP7 = osterix; TNFα = tumor necrosis factor alpha; VEGF = vascular endothelial growth factor; Wnt = wingless-related integration site. Adapted from [5] with permission.

Figure 4.

Nanoparticle properties affecting the adsorption of proteins in vivo, which significantly effect biodistribution and delivery efficacy. Reproduced with permission from [140].