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Stepwise Administration of Bone-Targeted Lipid Nanoparticles Encapsulating Valproic Acid and TUDCA Facilitates In Vivo Direct Reprogramming for Osteoporosis Treatment
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Stepwise Administration of Bone-Targeted Lipid Nanoparticles Encapsulating Valproic Acid and TUDCA Facilitates In Vivo Direct Reprogramming for Osteoporosis Treatment
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Journal Article
Stepwise Administration of Bone-Targeted Lipid Nanoparticles Encapsulating Valproic Acid and TUDCA Facilitates In Vivo Direct Reprogramming for Osteoporosis Treatment
2025
Overview
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.
Publisher
Springer Nature Singapore,Springer Nature B.V,Springer,한국조직공학과 재생의학회
