Reversing Immune Checkpoint Inhibitor-Associated Cardiotoxicity via Bioorthogonal Metabolic Engineering-Driven Extracellular Vesicle Redirecting.
Miao FanXing ZhangHuifang LiuLanya LiFei WangLi LuoXiaohan ZhouXing-Jie LiangJinchao ZhangZhenhua LiPublished in: Advanced materials (Deerfield Beach, Fla.) (2024)
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.
Keyphrases
- high glucose
- type diabetes
- diabetic rats
- heart failure
- left ventricular
- drug induced
- signaling pathway
- cardiovascular disease
- oxidative stress
- endothelial cells
- stem cells
- coronary artery disease
- mesenchymal stem cells
- insulin resistance
- transcription factor
- cardiovascular events
- bone marrow
- adipose tissue
- amino acid
- skeletal muscle
- combination therapy
- cell therapy