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Introduction <p>Intervertebral disc degeneration (IVDD) is a predominant cause of low back pain, and mesenchymal stem cell (MSC) transplantation represents a promising therapeutic strategy. However, its efficacy is severely limited by the harsh oxidative microenvironment of the degenerative disc, which rapidly triggers ferroptosis, an iron-dependent form of cell death, in transplanted MSCs.</p> Method <p>This review critically appraised current ferroptosis-inhibition strategies, highlighting their transient or single-axis limitations. We then synthesized a hierarchical framework for engineering robust MSC resistance, progressing from dual-target gene circuits and genetic-pharmacological alliances to smart, protective biomaterial niches.</p> Result <p>Conventional approaches provide only partial protection. In contrast, advanced multi-layered strategies, including dual-target gene circuits (e.g., the Prominin-2/FBXO22/BACH1 axis) potentiated by genetic-pharmacological alliances (e.g., with TBE56), confer superior, cell-intrinsic resilience, increasing MSC survival by approximately 1.5-fold and significantly improving regenerative outcomes in IVDD models. Furthermore, encapsulating engineered MSCs in responsive biomaterials establishes a protective niche, ensuring sustained function.</p> Conclusion <p>The paradigm is shifting from passive protection to active cellular empowerment. Engineering MSCs with multi-layered, comprehensive ferroptosis shielding is fundamental to unlocking their full therapeutic potential. This engineered cellular empowerment strategy represents a paradigm shift from palliative care to potentially curative, regenerative treatment for IVDD, with the potential to fundamentally change clinical management by addressing the root cause of MSC therapy failure.</p>

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Multi-layered integrated shielding: engineering ferroptosis-resistant mesenchymal stem cells for precision therapy of intervertebral disc degeneration

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Yuzhu Xu,
  • Zhanyang Qian,
  • Mingliang Ji,
  • Jun Lu

摘要

Introduction

Intervertebral disc degeneration (IVDD) is a predominant cause of low back pain, and mesenchymal stem cell (MSC) transplantation represents a promising therapeutic strategy. However, its efficacy is severely limited by the harsh oxidative microenvironment of the degenerative disc, which rapidly triggers ferroptosis, an iron-dependent form of cell death, in transplanted MSCs.

Method

This review critically appraised current ferroptosis-inhibition strategies, highlighting their transient or single-axis limitations. We then synthesized a hierarchical framework for engineering robust MSC resistance, progressing from dual-target gene circuits and genetic-pharmacological alliances to smart, protective biomaterial niches.

Result

Conventional approaches provide only partial protection. In contrast, advanced multi-layered strategies, including dual-target gene circuits (e.g., the Prominin-2/FBXO22/BACH1 axis) potentiated by genetic-pharmacological alliances (e.g., with TBE56), confer superior, cell-intrinsic resilience, increasing MSC survival by approximately 1.5-fold and significantly improving regenerative outcomes in IVDD models. Furthermore, encapsulating engineered MSCs in responsive biomaterials establishes a protective niche, ensuring sustained function.

Conclusion

The paradigm is shifting from passive protection to active cellular empowerment. Engineering MSCs with multi-layered, comprehensive ferroptosis shielding is fundamental to unlocking their full therapeutic potential. This engineered cellular empowerment strategy represents a paradigm shift from palliative care to potentially curative, regenerative treatment for IVDD, with the potential to fundamentally change clinical management by addressing the root cause of MSC therapy failure.