Serum-tolerant polymeric complex for stem-cell transfection and neural differentiation
Yi Jin, Guochen Han, Yuemei Gao, Hao Cheng, Chenhua Sun, Ni Jiang, Jianping Zhou, Huaqing Zhang, Yang Ding
Abstract
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. Stem cell therapies have huge potential but face challenges. Here, the authors report on a serum-tolerant boronated polyethyleneimine assembly with apolipoprotein corona, to carry miRNA-124 and all-trans retinoic acid derivative to achieve efficient stem-cell transfection and neural differentiation.