Regulatory mechanisms of dynamic mitochondria–macrophage interactions in myocardial ischemia–reperfusion injury and materials-based targeted therapy

Myocardial ischemia–reperfusion injury (MIRI) is a major determinant of prognosis in ischemic heart disease. Its pathological basis extends beyond cardiomyocyte injury to include the release of mitochondrial stress signals and remodeling of the immune microenvironment. This review focuses on the “mitochondria–immune axis” and describes how mitochondria shift from metabolic hubs to sources of danger signals under reperfusion stress. Oxidative stress and calcium overload can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), resulting in loss of membrane potential, matrix swelling, and leakage of mitochondrial damage signals. These events contribute to necrosis, NLRP3 inflammasome activation, and pyroptosis-like responses. Under specific conditions, mitochondrial injury may also affect oxidative stress associated with ferroptosis. The recently proposed concept of mitoxyperilysis offers a new framework for linking localized mitochondrial oxidative damage to lytic cell death. However, its involvement in myocardial ischemia–reperfusion (MIR) and its causal relationship with mPTP opening require further investigation. Released mitochondrial damage-associated molecular patterns (mtDAMPs) can trigger cGAS–STING- or NLRP3-related stress responses within cardiomyocytes. They may also be taken up by macrophages and other myeloid cells, leading to nucleic acid sensing, inflammasome activation, and amplification of inflammatory cascades. Conversely, macrophages regulate the clearance of damaged mitochondria and the resolution of inflammation through efferocytosis, lysosomal degradation, immunometabolic reprogramming, and histone lactylation. Intercellular mitochondrial transfer mediated by tunneling nanotubes (TNTs) and extracellular vesicles (EVs) may contribute to metabolic compensation, debris clearance, and danger-signal propagation. However, its stage-specific roles in MIR remain unclear. Finally, this review summarizes environment-responsive, immune-camouflaged, and multistage targeted delivery platforms and discusses their therapeutic windows, delivery efficiency, safety, and standardization. Stage-specific modulation of the mitochondria–immune axis may guide the development of more clinically feasible interventions for MIRI.