Microenvironment‐Responsive Nanomedicine Enables Vertical Modulation of Mitochondrial Pathological Networks in Myocardial Ischemia–Reperfusion Injury

ABSTRACT Myocardial ischemia–reperfusion injury (MIRI) is a severe and largely unavoidable complication of reperfusion therapy and remains a major determinant of poor outcomes after acute myocardial infarction. Here, we developed a mitochondria‐targeted, ischemic microenvironment–responsive nanotherapeutic, termed Berberine/Isoliensinine‐loaded Melanin Nanocomposite (BIM), by co‐encapsulating the anti‐inflammatory agent berberine (BBR) and the anti‐apoptotic agent isoliensinine (ILS) within a melanin capsule with a controllable channel (MCC). Owing to its appropriate size, negative surface charge, and dual responsiveness to acidic pH and reactive oxygen species, BIM preferentially accumulates in injured myocardium and targets damaged mitochondria, enabling precise drug release at the pathological core. Through a structured pharmacological design, MCC scavenges mitochondrial reactive oxygen species, BBR suppresses inflammatory signaling, and ILS inhibits intrinsic apoptosis, together achieving vertical modulation of mitochondrial pathological networks. Consequently, BIM attenuates oxidative stress, limits inflammatory amplification, reduces cardiomyocyte apoptosis, and markedly decreases infarct size. These findings establish mitochondria‐centered vertical network modulation as a precise therapeutic strategy for MIRI.