Confounding results of engineered mesenchymal stem cells (MSCs) used as cellular vehicles has plagued technologies whereby success or failure of novel approaches may be dismissed or inaccurately ascribed solely to the biotechnology platform rather than suitability of the human donor. Polymeric materials were screened for non‐viral engineering of MSCs from multiple human donors to deliver bone morphogenic protein‐4 (BMP4), a protein previously investigated in clinical trials for glioblastoma (GBM) to combat a subpopulation of highly invasive and tumorigenic clones. A “smart technology” that target the migratory and stem‐like nature of GBM will require: (1) a cellular vehicle (MSC) which can scavenge and target residual cells left behind after surgical debulking and deliver; (2) anti‐glioma cargo (BMP4). Multiple MSC donors are safely engineered, though varied in susceptibility to accept BMP4 due to intrinsic characteristics revealed by their molecular signatures. Efficiency is compared via secretion, downstream signaling, differentiation, and anti‐proliferative properties across all donors. In a clinically relevant resection and recurrence model of patient‐derived human GBM, we demonstrate that nanoengineered MSCs are not “donor agnostic” and efficacy is influenced by the inherent suitability of the MSC to the cargo. Therefore, donor profiles hold greater influence in determining downstream outcomes than the technical capabilities of the engineering technology.

中文翻译：

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纳米工程患者来源的间充质干细胞在人胶质母细胞瘤小鼠切除和复发模型中的治疗潜力和影响


用作细胞载体的工程间充质干细胞 （MSC） 的混杂结果一直困扰着技术，因此新方法的成功或失败可能会被忽视或错误地完全归因于生物技术平台，而不是人类供体的适用性。筛选聚合物材料对来自多个人类供体的 MSC 进行非病毒工程改造，以递送骨形态发生蛋白-4 （BMP4），这是一种先前在胶质母细胞瘤 （GBM） 临床试验中研究的蛋白质，以对抗高度侵袭性和致瘤克隆的亚群。针对 GBM 的迁移和干细胞样性质的“智能技术”将需要：（1） 一种细胞载体 （MSC），它可以清除和靶向手术减瘤和分娩后留下的残留细胞;（2） 抗神经胶质瘤货物 （BMP4）。多个 MSC 供体经过安全改造，但由于分子特征揭示的内在特征，接受 BMP4 的易感性各不相同。通过所有供体的分泌、下游信号传导、分化和抗增殖特性来比较效率。在患者来源的人 GBM 的临床相关切除和复发模型中，我们证明了纳米工程 MSC 不是“与供体无关”的，并且疗效受 MSC 对货物的固有适用性的影响。因此，供体概况在决定下游结果方面比工程技术的技术能力具有更大的影响力。