Strategies for accelerating osteogenesis through nanoparticle-based DNA/mitochondrial damage repair

Abstract

The efficiency of gene therapy is often dictated by the gene delivery system. Cationic polymers are essential elements of gene delivery systems. The relatively cheap cationic polymer, polyethyleneimine, has high gene delivery efficiency and is often used for gene delivery. However, the efficiency of gene therapy with polyethyleneimine-pDNA polyplex (PEI) is low. Human mesenchymal stem cells transfected with polyethyleneimine and a plasmid carrying the important osteogenic differentiation gene runt-related transcription factor 2 (RUNX2) accumulated DNA double-strand breaks and mitochondrial damage proportional to the amount of polyethyleneimine, reducing viability. Genomic/cellular stabilizer mediating RUNX2 delivery (GuaRD), a new reagent incorporating RS-1 NPs developed in this study, promoted DNA repair and prevented the accumulation of cell damage, allowing the delivery of pRUNX2 into hMSCs. while maintaining genome and mitochondrial stability. DNA damage was significantly lower and the expression of DNA repair-related genes significantly higher with GuaRD than with PEI. In addition, GuaRD improved mitochondrial stability, decreased the level of reactive oxygen species, and increased mitochondrial membrane potential. Osteogenic extracellular matrix (ECM) expression and calcification were higher with GuaRD than with PEI, suggesting improved osteogenic differentiation. These results indicate that lowering the cytotoxicity of PEI and improving cell stability are key to overcoming the limitations of conventional gene therapy, and that GuaRD can help resolve these limitations.

Gallic Acid-Modified Polyethylenimine–Polypropylene Carbonate–Polyethylenimine Nanoparticles: Synthesis, Characterization, and Anti-Periodontitis Evaluation

“…The hydrophilic PEI chain segments, the “shells” of the nanoparticles, exhibit cytotoxicity due to the highly positively charged structure of the surface. Such cytotoxicity is manifested in DNA damage . The toxicity of PEI greatly limits the potential of PEI nanoparticles for gene delivery and gene therapy .…”

“…Such cytotoxicity is manifested in DNA damage. 69 The toxicity of PEI greatly limits the potential of PEI nanoparticles for gene delivery and gene therapy. 70 It is well established that modifying PEI nanoparticles with amines significantly reduces their cytotoxicity.…”

Bone regeneration strategies based on organelle homeostasis of mesenchymal stem cells

“…Herein, maintaining genomic stability of the nucleus is crucial for the treatment of inflammatory bone diseases. Recently, the inhibitory effect of RS-1 (3-(benzylaminosulfonyl)-4-bromo-N-(4bromophenyl) benzamide) on DNA damage during PEI-mediated gene therapy was explored (242). RS-1 has been implicated as a stimulator of RAD51 recombinase (RAD51), a key activator of proteins necessary for homologous recombination (HR) in the DNA repair process.…”

Poly(ethylenimine)-Cyclodextrin-Based Cationic Polymer Mediated HIF-1α Gene Delivery for Hindlimb Ischemia Treatment

“…Lowering the cytotoxicity and improving biocompatibility are important direction to optimize the PEIbased gene delivery vectors. 13 Cyclodextrins (CDs) are a sugar-related natural product, which has been reported applicated in gas capture, drug delivery, and food industries. 14,15 In our previous studies, low molecular weight PEI (MW 600) was cross-linked with β-cyclodextrin (β-CyD) to construct PEI600-CD (PC), which showed tremendous potential as gene and drug delivery vectors for cancer therapy with high biocompatibility and transfection efficiency.…”

“…However, their high cytotoxicity and low biocompatibility are the main limitations for their application in vivo. Lowering the cytotoxicity and improving biocompatibility are important direction to optimize the PEI-based gene delivery vectors . Cyclodextrins (CDs) are a sugar-related natural product, which has been reported applicated in gas capture, drug delivery, and food industries. , In our previous studies, low molecular weight PEI (MW 600) was cross-linked with β-cyclodextrin (β-CyD) to construct PEI600-CD (PC), which showed tremendous potential as gene and drug delivery vectors for cancer therapy with high biocompatibility and transfection efficiency. , Thus, PC was an ideal candidate for HIF-1α, which provides a good prospect for the treatment of ischemic stroke and is worthy of further exploration.…”