Whilst traditional strategies to increase transfection efficiency of non-viral systems aimed at modifying the vector or the polyplexes/lipoplexes, biomaterial-mediated gene delivery has recently sparked increased interest. This review aims at discussing biomaterial properties and unravelling underlying mechanisms of action, for biomaterial-mediated gene delivery. DNA internalisation and cytoplasmic transport are initially discussed. DNA immobilisation, encapsulation and surface-mediated gene delivery (SMD), the role of extracellular matrix (ECM) and topographical cues, biomaterial stiffness and mechanical stimulation are finally outlined. Endocytic pathways and mechanisms to escape the lysosomal network are highly variable. They depend on cell and DNA complex types but can be diverted using appropriate biomaterials. 3D scaffolds are generally fabricated via DNA immobilisation or encapsulation. Degradation rate and interaction with the vector affect temporal patterns of DNA release and transgene expression. In SMD, DNA is instead coated on 2D surfaces. SMD allows the incorporation of topographical cues, which, by inducing cytoskeletal re-arrangements, modulate DNA endocytosis. Incorporation of ECM mimetics allows cell type-specific transfection, whereas in spite of discordances in terms of optimal loading regimens, it is recognised that mechanical loading facilitates gene transfection. Finally, stiffer 2D substrates enhance DNA internalisation, whereas in 3D scaffolds, the role of stiffness is still dubious. Although it is recognised that biomaterials allow the creation of tailored non-viral gene delivery systems, there still are many outstanding questions. A better characterisation of endocytic pathways would allow the diversion of cell adhesion processes and cytoskeletal dynamics, in order to increase cellular transfection. Further research on optimal biomaterial mechanical properties, cell ligand density and loading regimens is limited by the fact that such parameters influence a plethora of other different processes (e.g. cellular adhesion, spreading, migration, infiltration, and proliferation, DNA diffusion and release) which may in turn modulate gene delivery. Only a better understanding of these processes may allow the creation of novel robust engineered systems, potentially opening up a whole new area of biomaterial-guided gene delivery for non-viral systems.

中文翻译：

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影响生物材料介导的质粒 DNA 递送的物理和机械线索：对非病毒递送系统的见解

虽然提高非病毒系统转染效率的传统策略旨在修饰载体或复合物/脂质复合物，但生物材料介导的基因递送最近引起了越来越多的兴趣。本综述旨在讨论生物材料的特性并阐明生物材料介导的基因传递的潜在作用机制。最初讨论了 DNA 内化和细胞质转运。最后概述了 DNA 固定、封装和表面介导的基因传递 (SMD)、细胞外基质 (ECM) 和地形线索、生物材料刚度和机械刺激的作用。逃离溶酶体网络的内吞途径和机制是高度可变的。它们取决于细胞和 DNA 复合物类型，但可以使用适当的生物材料进行转移。3D 支架通常通过 DNA 固定或封装来制造。降解率和与载体的相互作用会影响 DNA 释放和转基因表达的时间模式。在 SMD 中，DNA 被涂在 2D 表面上。SMD 允许结合地形线索，通过诱导细胞骨架重新排列，调节 DNA 内吞作用。ECM 模拟物的结合允许细胞类型特异性转染，而尽管在最佳加载方案方面存在不一致，但人们认识到机械加载有助于基因转染。最后，较硬的 2D 基底增强了 DNA 内化，而在 3D 支架中，刚度的作用仍然值得怀疑。尽管人们认识到生物材料允许创建定制的非病毒基因传递系统，但仍然存在许多悬而未决的问题。更好地表征内吞途径将允许转移细胞粘附过程和细胞骨架动力学，以增加细胞转染。对最佳生物材料机械性能、细胞配体密度和加载方案的进一步研究受到以下事实的限制：这些参数会影响过多的其他不同过程（例如细胞粘附、扩散、迁移、浸润和增殖、DNA 扩散和释放），这些过程可能反过来调节基因传递。只有更好地理解这些过程，才能创建新的稳健工程系统，从而为非病毒系统的生物材料引导基因递送开辟一个全新的领域。以增加细胞转染。对最佳生物材料机械性能、细胞配体密度和加载方案的进一步研究受到以下事实的限制：这些参数会影响过多的其他不同过程（例如细胞粘附、扩散、迁移、浸润和增殖、DNA 扩散和释放），这些过程可能反过来调节基因传递。只有更好地理解这些过程，才能创建新的稳健工程系统，从而为非病毒系统的生物材料引导基因递送开辟一个全新的领域。以增加细胞转染。对最佳生物材料机械性能、细胞配体密度和加载方案的进一步研究受到以下事实的限制：这些参数会影响过多的其他不同过程（例如细胞粘附、扩散、迁移、浸润和增殖、DNA 扩散和释放），这些过程可能反过来调节基因传递。只有更好地理解这些过程，才能创建新的稳健工程系统，从而为非病毒系统的生物材料引导基因递送开辟一个全新的领域。扩散、迁移、浸润和增殖、DNA 扩散和释放），这可能反过来调节基因传递。只有更好地理解这些过程，才能创建新的稳健工程系统，从而为非病毒系统的生物材料引导基因递送开辟一个全新的领域。扩散、迁移、浸润和增殖、DNA 扩散和释放），这可能反过来调节基因传递。只有更好地理解这些过程，才能创建新的稳健工程系统，从而为非病毒系统的生物材料引导基因递送开辟一个全新的领域。