In situ self-assembled stimulus-responsive and conductive hydrogel modulate myocardial infarction inflammatory homeostasis via PPARα/NFκB signaling and enhance the therapeutic efficacy of hiPSC-CMs.

Stem cell therapies are emerging as promising strategies for repair after myocardial infarction (MI), but the repair efficacy is limited by the poor cardiac microenvironment represented by the inflammatory response, as well as oxidative stress, and adverse electrical coupling. Here, we developed an injectable supramolecular hydrogel (HCPA) that modulates the infarct microenvironment and accelerates myocardial repair by encapsulating human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs). HCPA hydrogel not only exhibited excellent reactive oxygen species (ROS) response in order to minimize oxidative stress but also possessed desirable electrical conductivity for the reintegration of electrical impulses. Critically, RNA sequencing demonstrated that the PPARα/NFκB pathway contributed significantly to the HCPA hydrogel-promoted macrophage polarization from M1-type to M2-type, thus alleviating inflammatory responses. HCPA hydrogel harboring hiPSC-CMs increased retention of hiPSC-CMs and improved cardiac function in MI mice. This study represents a new integrated therapeutic option for MI and provides insights for the development of novel biomaterials in the field of tissue engineering.