| Summary: | Natural extracellular matrix (ECM) is highly heterogeneous and anisotropic due to the existence of biomacromolecule bundles and pores. Hydrogels have been proposed as ideal carriers for therapeutic cells and drugs in tissue engineering and regenerative medicine. However, most of the homogeneous and isotropic hydrogels cannot fully emulate the hierarchical properties of natural ECM, including the dynamically spatiotemporal distributions of biochemical and biomechanical signals. Biomimetic hierarchical nanocomposite hydrogels have emerged as potential candidates to better recapitulate natural ECM by introducing various nanostructures, such as nanoparticles, nanorods, and nanofibers. Moreover, the nanostructures in nanocomposite hydrogels can be engineered as stimuli-responsive actuators to realize the desirable control of hydrogel properties, thereby manipulating the behaviors of the encapsulated cells upon appropriate external stimuli. In this review, we present a comprehensive summary of the main strategies to construct biomimetic hierarchical nanocomposite hydrogels with an emphasis on the rational design of local hydrogel properties and their stimuli-responsibility. We then highlight cell fate decisions in engineered nanocomposite niches and their recent development and challenges in biomedical applications.
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