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Background: <p>The ultimate goal of regenerative medicine is to restore damaged tissues to a healthy state in the body. Direct reprogramming, also referred to as transdifferentiation, holds significant therapeutic potential by converting abundant somatic cells, such as fibroblasts, into functionally distinct cell types for tissue regeneration. Despite its potential applications in regenerative medicine, direct reprogramming faces major challenges, including low efficiency and poor <i>In vivo</i> applicability. In this study, we propose a novel therapeutic strategy for osteoporosis based on <i>In vivo</i> direct reprogramming using a stepwise delivery approach that first enhances cellular stemness and subsequently induces osteogenic transdifferentiation. Enhancing stemness in lineage-committed cells facilitates their conversion into other functional cell types.</p> Method: <p>To investigate the efficiency of direct reprogramming via stepwise delivery, we utilized valproic acid (VPA) and tauroursodeoxycholic acid (TUDCA) as reprogramming and bone-stimulating factors, respectively. VPA increased the expression of stemness genes, including Oct4, Nanog, and Sox2, and subsequent treatment of TUDCA enhanced the expression of osteogenic genes in the mouse fibroblast. Targeted delivery of these factors to fibroblasts surrounding bone tissue, enabling subsequent direct reprogramming into osteoblasts, was achieved using bisphosphonate (BP)-conjugated lipid nanoparticles as carriers.</p> Results: <p>Our findings demonstrate that sequential induction of cell reprogramming and tissue regeneration through stepwise administration of VPA and TUDCA significantly enhances therapeutic efficacy in a mouse model of osteoporosis compared to their simultaneous administration.</p> Conclusion: <p>This stepwise bone-targeted drug delivery system presents a promising strategy for osteoporosis treatment via <i>In vivo</i> direct reprogramming.</p> Graphical abstract <p></p> <p>Stepwise administration of VPA-LNPs and TUDCA-LNPs enhances <i>In vivo</i> direct reprogramming for osteoporosis therapy.</p>

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Stepwise Administration of Bone-Targeted Lipid Nanoparticles Encapsulating Valproic Acid and TUDCA Facilitates In Vivo Direct Reprogramming for Osteoporosis Treatment

  • 期刊论文

  • 发表日期：

    2025年6月24日

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  • Hyoeun Park,
  • Woong Jin Cho,
  • Jiseong Kim,
  • Hyejong Choi,
  • Inho Baek,
  • Youngjin Kim,
  • Deogil Kim,
  • Byoung Ju Kim,
  • Yoshie Arai,
  • Soo-Hong Lee

摘要

Background:

The ultimate goal of regenerative medicine is to restore damaged tissues to a healthy state in the body. Direct reprogramming, also referred to as transdifferentiation, holds significant therapeutic potential by converting abundant somatic cells, such as fibroblasts, into functionally distinct cell types for tissue regeneration. Despite its potential applications in regenerative medicine, direct reprogramming faces major challenges, including low efficiency and poor In vivo applicability. In this study, we propose a novel therapeutic strategy for osteoporosis based on In vivo direct reprogramming using a stepwise delivery approach that first enhances cellular stemness and subsequently induces osteogenic transdifferentiation. Enhancing stemness in lineage-committed cells facilitates their conversion into other functional cell types.

Method:

To investigate the efficiency of direct reprogramming via stepwise delivery, we utilized valproic acid (VPA) and tauroursodeoxycholic acid (TUDCA) as reprogramming and bone-stimulating factors, respectively. VPA increased the expression of stemness genes, including Oct4, Nanog, and Sox2, and subsequent treatment of TUDCA enhanced the expression of osteogenic genes in the mouse fibroblast. Targeted delivery of these factors to fibroblasts surrounding bone tissue, enabling subsequent direct reprogramming into osteoblasts, was achieved using bisphosphonate (BP)-conjugated lipid nanoparticles as carriers.

Results:

Our findings demonstrate that sequential induction of cell reprogramming and tissue regeneration through stepwise administration of VPA and TUDCA significantly enhances therapeutic efficacy in a mouse model of osteoporosis compared to their simultaneous administration.

Conclusion:

This stepwise bone-targeted drug delivery system presents a promising strategy for osteoporosis treatment via In vivo direct reprogramming.

Graphical abstract

Stepwise administration of VPA-LNPs and TUDCA-LNPs enhances In vivo direct reprogramming for osteoporosis therapy.