Background The niche of tissue development in vivo involves the growth matrix, biophysical cues and cell-cell interactions. Although natural extracellular matrixes may provide good supporting for seeding cells in vitro, it is evitable to destroy biophysical cues during decellularization. Reconstructing the bioactivities of extracellular matrix-based scaffolds is essential for their usage in tissue repair. Results In the study, a hybrid hydrogel was developed by incorporating single-wall carbon nanotubes (SWCNTs) into heart-derived extracellular matrixes. Interestingly, insoluble SWCNTs were well dispersed in hybrid hydrogel solution via the interaction with extracellular matrix proteins. Importantly, an augmented integrin-dependent niche was reconstructed in the hybrid hydrogel, which could work like biophysical cues to activate integrin-related pathway of seeding cells. As supporting scaffolds in vitro, the hybrid hydrogels were observed to significantly promote seeding cell adhesion, differentiation, as well as structural and functional development towards mature cardiac tissues. As injectable carrier scaffolds in vivo, the hybrid hydrogels were then used to delivery stem cells for myocardial repair in rats. Similarly, significantly enhanced cardiac differentiation and maturation(12.5 ± 2.3% VS 32.8 ± 5%) of stem cells were detected in vivo, resulting in improved myocardial regeneration and repair. Conclusions The study represented a simple and powerful approach for exploring bioactive scaffold to promote stem cell-based tissue repair. Graphic abstract

Myocardial ischaemia is pathologically complicated; various changes in intracellular and extracellular microenvironments make it essential to develop a smart drug system with multiple stimulus responses to adapt to the complex process. Inspired by the cobweb, this study designs a microreticular nanosystem that adheres to tissue and is sequentially responsive to multiple stimuli in the ischaemic microenvironment. The nanosystem is fabricated from hyaluronic acid (HA), ROS‐responsive B‐PDEA, and hypoxia‐sensitive VEGF‐expressing plasmids (EPODNA) through electrostatic interactions. After intramyocardial injection, the tissue‐adhesive property of the nanosystem will significantly decrease its acute loss from the injection site. Extracellularly, the microreticular nanosystem first responds to activated hyaluronidase (hyal), releasing HA for microenvironment regulation and B‐PDEA/DNA nanoparticles (NP) with high transfection efficiency for cardiac cells. Intracellularly, ROS sequentially induced B‐PDEA/DNA NP dissociation, consuming some ROS to attenuate oxidative stress and releasing DNA to promote its expression. Meanwhile, local hypoxia significantly activates VEGF expression in plasmids for myocardial revascularization and repair. The function of the microreticular nanosystem is systematically evaluated in vitro. In a rat model of myocardial infarction, treatment with the microreticular nanosystem significantly promotes functional and structural improvements. Collectively, the study provides a promising smart nanosystem to promote tissue repair after complex damage.