Reversing Immune Checkpoint Inhibitor–Associated Cardiotoxicity via Bioorthogonal Metabolic Engineering–Driven Extracellular Vesicle Redirecting

Abstract

The cardiotoxicity induced by immune checkpoint inhibitors (ICIs) is associated with high mortality rates. T cells play an important role in ICI‐induced cardiac injury. The inhibition of local T‐cell activity is considered an effective strategy for alleviating ICI‐related cardiotoxicity. Tumor‐derived extracellular vesicles (EVs) contribute to immunosuppression via PD‐L1 overexpression. In this study, a bioorthogonal metabolic engineering–driven EV redirecting (Biomeder) strategy for in situ engineered EVs with myocardial‐targeting peptides is developed. Accumulated tumor‐derived EV (TuEVs) reverses the immune environment in the heart by increasing PD‐L1 levels in cardiomyocytes and/or by directly inhibiting T‐cell activity. More importantly, it is found that the redirection of TuEVs further disrupts immunosuppression in tumors, which facilitates anti‐tumor activity. Thus, redirecting TuEVs to the heart simultaneously enhances the antitumor efficacy and safety of ICI‐based therapy. Furthermore, the Biomeder strategy is successfully expanded to prevent ICI‐induced type 1 diabetes. This Biomeder technique is a universal method for the treatment of various ICI‐related adverse events.