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<p>Modulating trained immunity while simultaneously initiating regenerative cues presents a significant challenge in large bone defect therapy. This study introduces a cell-free approach utilizing a 3D microenvironment-responsive scaffold to orchestrate immune reprogramming. To mitigate maladaptive trained immunity and activate regenerative signaling, a composite fibrous scaffold is functionalized with immune-engineered exosomes derived from inflammation-primed mesenchymal stem cells (PSS-iEXO) in a reactive oxygen species (ROS)-responsive manner. The PSS-iEXO scaffolds incorporate boronic ester linkages as ROS-sensitive moieties, enabling rapid, dynamic, and “on-demand” exosome release in response to elevated ROS levels characteristic of the early inflammatory phase post-injury, thereby initiating regeneration. In vitro and in vivo analyses reveal that these scaffolds precisely target and modulate maladaptive trained immunity, reprogramming immune responses by shifting macrophage polarization from a hyperactivated type I phenotype to a balanced state while promoting CD4<sup>+</sup> regulatory T cell activation—both critical for coupling angiogenesis and osteogenesis. Mechanistic insights highlight the role of engineered exosomes in enhancing mitochondrial function and oxidative phosphorylation in macrophages, establishing a cell-free immune-regenerative niche for large bone defect therapy.</p> Graphical Abstract <p>Schematic diagram of the fabrication, function, and mechanism of ROS-responsive 3D electrospun nanofiber scaffolds loaded with immunoengineered exosomes (PSS-iEXO) for promoting large bone repair.</p> <p></p>

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A Targeting Trained Immunity Nanofiber Scaffold for Large Bone Defect Repair

  • 期刊论文

  • 发表日期：

    2025年5月12日

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  • Jingdi Zhan,
  • Zhuolin Chen,
  • Junyan Liu,
  • Qiming Pang,
  • Mingjie Lei,
  • Jiacheng Liu,
  • Yang Song,
  • Wei Huang,
  • Lili Dong

摘要

Modulating trained immunity while simultaneously initiating regenerative cues presents a significant challenge in large bone defect therapy. This study introduces a cell-free approach utilizing a 3D microenvironment-responsive scaffold to orchestrate immune reprogramming. To mitigate maladaptive trained immunity and activate regenerative signaling, a composite fibrous scaffold is functionalized with immune-engineered exosomes derived from inflammation-primed mesenchymal stem cells (PSS-iEXO) in a reactive oxygen species (ROS)-responsive manner. The PSS-iEXO scaffolds incorporate boronic ester linkages as ROS-sensitive moieties, enabling rapid, dynamic, and “on-demand” exosome release in response to elevated ROS levels characteristic of the early inflammatory phase post-injury, thereby initiating regeneration. In vitro and in vivo analyses reveal that these scaffolds precisely target and modulate maladaptive trained immunity, reprogramming immune responses by shifting macrophage polarization from a hyperactivated type I phenotype to a balanced state while promoting CD4+ regulatory T cell activation—both critical for coupling angiogenesis and osteogenesis. Mechanistic insights highlight the role of engineered exosomes in enhancing mitochondrial function and oxidative phosphorylation in macrophages, establishing a cell-free immune-regenerative niche for large bone defect therapy.

Graphical Abstract

Schematic diagram of the fabrication, function, and mechanism of ROS-responsive 3D electrospun nanofiber scaffolds loaded with immunoengineered exosomes (PSS-iEXO) for promoting large bone repair.