Injectable and pH‐Activated Self‐Feedback Hydrogel Encapsulating Stem Cells for Augmented Acute Myocardial Infarction Therapy

Hydrogels encapsulating stem cells represent a promising strategy for enhancing cardiac function following acute myocardial infarction (AMI). However, hostile post-infarct microenvironments, characterized by oxidative stress and ischemia, significantly reduce stem cell retention and survival rates. Herein, an intramyocardially injectable and pH-responsive (2' Z, 3' E)-6-Bromoindirubin-3'-oxime (BIO)-N-adipose-derived stem cells (ADSCs)-Matrigel system is developed for treating AMI. Encapsulated ADSCs exhibited a high retention rate in myocardial tissue. Furthermore, BIO-N exhibited a self-feedback function, enabling it to modulate the release of BIO in response to pH changes in the microenvironment during the progression of AMI. This system effectively protected stem cells and cardiomyocytes from ROS-induced injury while enhancing the therapeutic efficacy of ADSCs by improving their paracrine function. Subsequently, it is demonstrated that the BIO-N-ADSCs-Matrigel system significantly reduced infarction size, mitigated fibrosis, and enhanced local angiogenesis in a rat model of AMI. The self-feedback functional BIO-N-ADSCs-Matrigel system can effectively mitigate local oxidative stress, enhance the survival rate and therapeutic efficacy of stem cells, and improve the viability of cardiomyocytes for AMI treatment.