Redox‐Respo n sive Tellurium‐Bridged Covalent Organic Frameworks/PEG Composites for Targeted Therapy of Diabetic Cardiomyopathy

Abstract Diabetic cardiomyopathy, a major complication of diabetes, is strongly associated with elevated levels of glycated hemoglobin (HbA1c) and reactive oxygen species (ROS). However, effective clinical strategies to simultaneously lower HbA1c and ROS levels remain elusive, primarily due to the lack of therapeutic agents that can efficiently and synergistically interact with both biological macromolecules and small reactive molecules. To tackle this challenge, a redox‐responsive tellurium‐bridged covalent organic framework (Te‐COF) is developed whose surface is functionalized with hydrazine‐bonded polyethylene glycol (PEG), yielding a series of three emissive Te‐COF@PEG nanocomposites with varying PEG molecular weights (Te‐COF@PEG, M W = 600, 2000, 6000 Da). In vitro studies demonstrate that Te‐COF@PEG composites efficiently remove HbA1c and total glycated protein from the plasma of diabetic patients, significantly lowering blood glucose levels without affecting serum levels of total proteins, lipids, and apolipoproteins. Among the composites, Te‐COF@PEG2000 exhibits the most promising therapeutic effects in diabetic mouse and rabbit models, including a significant reduction in fasting blood glucose, HbA1c, and inflammatory factor levels. Importantly, Te‐COF@PEG2000 induces macrophage polarization towards M2 phenotype, inhibits cardiomyocyte apoptosis, scavenges excess ROS, and synergistically improves myocardial injury. This study unlocks the immense potential of COF@polymer nanocomposites as a multifunctional platform for targeted diabetic cardiomyopathy therapy.