A Pathology‐Instructed Theranostic Platform with Mechanoadaptive and ROS‐Powered Nanobreathing Functions for Precision Myocardial Repair

ABSTRACT Current myocardial infarction (MI) biomaterials often fail to dynamically adapt to the evolving pathological microenvironment (e.g., ROS bursts, hypoxia), lacking both mechanical compatibility and in situ feedback. To overcome these limitations, we developed an albumin hydrogel platform (BST) with a closed‐loop pathological response system. BST is a pH‐responsive hydrogel, functionalized with MRI/CT probes and loaded with mitochondria‐targeted CAT‐SOD enzyme nanogels (CSDT). It forms a self‐repairing scaffold with high shear viscosity (∼300 Pa·s), elasticity, and cardiac‐like mechanics (∼7.5 kPa), stabilizing the infarct wall. Hypoxia‐induced acidosis triggers the release of CSDT nanogels and albumin, enabling mitochondrial ROS scavenging and O ₂ generation, while albumin restores tissue osmotic balance. These actions collectively alleviate oxidative stress, modulate immune responses, and promote cardiomyocyte survival by enhancing autophagy and anti‐apoptotic pathways. This inside‐out feedback mechanism reverses oxidative stress and hypoxia, shifts macrophages to a reparative M2 phenotype, and increases angiogenesis by ∼2.5‐fold. In an MI mouse model, BST, with programmable biodegradation (∼3 weeks), restored left ventricular ejection fraction to ∼70% of sham group and improved 28‐day survival by ∼2.5‐fold. Furthermore, BST enables real‐time MRI/CT tracking of material retention and tissue repair dynamically, permitting spatiotemporal control of the infarct microenvironment and advancing precision MI therapy toward clinical translation.