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<p>Mesenchymal stem cell (MSC) therapy holds promise in biomedical applications but faces challenges in efficient transfection without compromising cell viability. Here, we show a serum-tolerant MSC transfection nanotool, APOs@BP, composed of an apolipoprotein (APO) corona and a boronated polyethyleneimine (BP) core. The APOs corona’s serum-protein resistance and cytomembrane affinity enable APOs@BP to achieve 10.4-fold higher transfection efficiency and improved cytocompatibility in serum-containing medium compared to high-molecular-weight polycationic transfectants. For MSC neural differentiation, miRNA-124 and all-trans retinoic acid derivative (atRAN) are further loaded into APOs@BP, forming a polymeric complex for sequential drug release triggered by lysosomal acid and cytosolic reactive oxygen species post-transplantation. Transcriptomic analysis confirms that this system enhances MSC neural differentiation through sequential activation of atRAN-induced differentiation potential and miRNA-124-directed neurogenesis via cGMP-PKG, MAPK, and PI3K-Akt pathways. Transplantation of engineered MSCs reconstructs neural circuits and alleviates cognitive impairment in Alzheimer’s disease model mice. Collectively, this system provides a robust and convenient method for MSC-based regenerative medicine.</p>

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Serum-tolerant polymeric complex for stem-cell transfection and neural differentiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月27日

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  • Yi Jin,
  • Guochen Han,
  • Yuemei Gao,
  • Hao Cheng,
  • Chenhua Sun,
  • Jiang Ni,
  • Jianping Zhou,
  • Huaqing Zhang,
  • Yang Ding

摘要

Mesenchymal stem cell (MSC) therapy holds promise in biomedical applications but faces challenges in efficient transfection without compromising cell viability. Here, we show a serum-tolerant MSC transfection nanotool, APOs@BP, composed of an apolipoprotein (APO) corona and a boronated polyethyleneimine (BP) core. The APOs corona’s serum-protein resistance and cytomembrane affinity enable APOs@BP to achieve 10.4-fold higher transfection efficiency and improved cytocompatibility in serum-containing medium compared to high-molecular-weight polycationic transfectants. For MSC neural differentiation, miRNA-124 and all-trans retinoic acid derivative (atRAN) are further loaded into APOs@BP, forming a polymeric complex for sequential drug release triggered by lysosomal acid and cytosolic reactive oxygen species post-transplantation. Transcriptomic analysis confirms that this system enhances MSC neural differentiation through sequential activation of atRAN-induced differentiation potential and miRNA-124-directed neurogenesis via cGMP-PKG, MAPK, and PI3K-Akt pathways. Transplantation of engineered MSCs reconstructs neural circuits and alleviates cognitive impairment in Alzheimer’s disease model mice. Collectively, this system provides a robust and convenient method for MSC-based regenerative medicine.