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<p>Amiloride improves the gene-transfection efficiency of octa-arginine (R8)-modified calcium phosphate (CaP) nanoparticles by modulating intracellular pH and calcium ion dynamics; however, the underlying mechanisms remain poorly understood. This study evaluated the in vitro and in vivo gene-transfection efficiency and osteogenic potential of R8-modified CaP nanoparticles combined with amiloride. In vitro experiments using MC3T3-E1 cells and rat bone marrow-derived cells revealed that amiloride increased transfection efficiency but also exhibited cytotoxic effects. Mechanistically, amiloride reduced intracellular pH and increased calcium concentration, leading to the aggregation of lysosomal contents toward the nucleus, whereas R8 application partially mitigated these pH changes. In vivo, collagen scaffolds incorporating R8-modified CaP carrying bone morphogenetic protein-2 (BMP-2)-encoding plasmid DNA, when combined with amiloride, demonstrated the highest local BMP-2 concentration and significantly enhanced bone formation in a rat calvarial defect model without severe inflammation. Although the volume of new bone formed via this gene-transfection approach was smaller than that achieved with 2&#xa0;µg of exogenous recombinant BMP-2 protein, the system demonstrated a significant synergistic effect. These findings suggest that R8-modified CaP nanoparticles combined with amiloride provide a promising strategy for enhancing gene-based bone regeneration through controlled intracellular dynamics.</p>

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Octa-arginine-modified calcium phosphate nanoparticles with amiloride enhance gene delivery and bone augmentation in rat calvaria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Taichi Tenkumo,
  • Rie Koide,
  • Longshuang Hu,
  • Ziqi Xie,
  • Juan Ramón Vanegas Sáenz,
  • Nobuhiro Yoda

摘要

Amiloride improves the gene-transfection efficiency of octa-arginine (R8)-modified calcium phosphate (CaP) nanoparticles by modulating intracellular pH and calcium ion dynamics; however, the underlying mechanisms remain poorly understood. This study evaluated the in vitro and in vivo gene-transfection efficiency and osteogenic potential of R8-modified CaP nanoparticles combined with amiloride. In vitro experiments using MC3T3-E1 cells and rat bone marrow-derived cells revealed that amiloride increased transfection efficiency but also exhibited cytotoxic effects. Mechanistically, amiloride reduced intracellular pH and increased calcium concentration, leading to the aggregation of lysosomal contents toward the nucleus, whereas R8 application partially mitigated these pH changes. In vivo, collagen scaffolds incorporating R8-modified CaP carrying bone morphogenetic protein-2 (BMP-2)-encoding plasmid DNA, when combined with amiloride, demonstrated the highest local BMP-2 concentration and significantly enhanced bone formation in a rat calvarial defect model without severe inflammation. Although the volume of new bone formed via this gene-transfection approach was smaller than that achieved with 2 µg of exogenous recombinant BMP-2 protein, the system demonstrated a significant synergistic effect. These findings suggest that R8-modified CaP nanoparticles combined with amiloride provide a promising strategy for enhancing gene-based bone regeneration through controlled intracellular dynamics.