Precise modulation of pathological networks in myocardial ischemia-reperfusion injury: Advances in multi-target nanomedicine strategies

Myocardial ischemia-reperfusion injury (MIRI) is driven by a cascade-amplified and spatiotemporally dynamic network involving oxidative stress, calcium overload, mitochondrial dysfunction, inflammation, and regulated cell death. Because these processes interact and change across injury stages and myocardial regions, single-target therapies often provide incomplete protection. This review presents a network-to-design framework for nanomedicine-enabled multi-target intervention. Four complementary paradigms are discussed: multi-cargo co-delivery, multifunctional material-based intervention, hierarchical tissue/cell/organelle targeting, and stimuli-responsive or sequentially programmed intervention. We analyze how nanocarrier properties, targeting mechanisms, and release kinetics can coordinate therapeutic targets with the relevant site and treatment window. Representative preclinical advances, evidence limitations, and major translational barriers are critically evaluated, including cardiac delivery efficiency, pharmacokinetics, biosafety, manufacturing consistency, and regulatory requirements. This framework is intended to support more rigorous and clinically relevant nanomedicine design for MIRI.