Assessment of hESC-IMRC-Exo for Cardiac and Cerebral Injuries Post-Cardiac Arrest Resuscitation: Safety, Pharmacokinetics, and Efficacy.

Cardiac arrest (CA) is a leading cause of death globally. Exosomes derived from mesenchymal stem cells exhibit favourable production, storage, and safety characteristics, making them a promising alternative for post-CA resuscitation. We assessed the safety, biodistribution, and protective effects of human embryonic stem cell-derived immunity-and-matrix regulatory cells (hESC-IMRC-Exo) for post-CA resuscitation cardiac/cerebral injuries, and preliminarily explored its underlying molecular mechanism. The biotoxicity of IMRC-Exo was evaluated in AC16 and HT22 cells and in mice; its biodistribution was traced using fluorescently labelled IMRC-Exo. Protective effects were examined in H/R-treated cells and rat and swine CA models. We found that IMRC-Exo did not induce apoptosis or oxidative stress in AC16 or HT22 cells. IMRC-Exo was also safe in mice, with normal body weight, blood indices, and histopathology. Pharmacokinetic analysis revealed rapid multi-organ distribution, peaking at 24 h with a 7-day half-life. For efficacy study, IMRC-Exo reduced LDH release, ROS levels, and apoptosis in H/R-treated cells. In rat, IMRC-Exo dose-dependently (0.5×, 1×, 2×) reduced serum biomarkers, improved neurological function, and attenuated inflammation. In swine, single-dose IMRC-Exo (1×) reduced injury biomarkers, improved neurological function, and attenuated inflammation. Furthermore, in a separate rat group, IMRC-Exo improved 7-day survival and neurological function. Mechanistically, the protective effects of IMRC-Exo were mediated by its secreted miR-21-5p, which attenuated H/R-induced apoptosis and inflammation by targeting PDCD4. This study demonstrated IMRC-Exo, a safe and effective therapeutic, distributed rapidly via the bloodstream to target organs and protected against post-resuscitation cardiac/cerebral injuries, potentially through the miR-21-5p/PDCD4 axis.