Clinically, ischemic diseases represent a leading cause of global mortality and disability, affecting vital organs including the heart, brain, liver, and kidneys [1], [2], [3], [4]. Although reperfusion is indispensable for tissue survival after ischemia, it frequently precipitates secondary injury cascades characterized by oxidative stress [5], [6], calcium overload [7], [8], inflammatory responses [9], [10], [11], and apoptosis [12], [13], [14], thereby driving cellular injury and poor prognosis [15], [16]. Accordingly, in myocardial infarction (MI), acute ischemic stroke (AIS), acute kidney injury (AKI), liver transplantation, and spinal cord ischemia, I/R injury remains a major determinant of organ dysfunction and mortality [17], [18], [19]. Nevertheless, the inherent complexity and unpredictable nature of I/R injury continue to pose formidable challenges for its effective prevention and treatment.
Mitochondrial dysfunction has emerged as a critical mechanism in I/R injury, driving cell death through multiple pathological pathways [20], [21]. Consequently, protecting mitochondrial function represents a promising therapeutic strategy to mitigate I/R injury. In response to mitochondrial impairment, cells activate mitophagy, a selective form of autophagy that targets and removes damaged mitochondria. As an adaptive mitochondrial quality control mechanism, mitophagy plays a central role in maintaining mitochondrial homeostasis and energy metabolism [22], [23]. However, mitophagy is not always beneficial. When it is appropriately activated and coupled with intact autophagic flux, it facilitates the clearance of dysfunctional mitochondria. In contrast, dysregulated or excessive activation may lead to mitochondrial depletion and energy failure, which in turn exacerbates cell death and tissue injury [24], [25]. These features render the intensity, timing, and autophagic flux competence of mitophagy critical considerations for therapeutic intervention.
Due to the high complexity of the lesion microenvironment and the heterogeneity of spatiotemporal regulation of mitophagy. Precisely controlling the intensity and timing of mitophagy to achieve optimal tissue protection remains a critical challenge. In this context, the rapid development of nanomedicine has provided not only innovative approaches for precise mitophagy modulation, but also a conceptual framework for addressing the spatiotemporal constraints that govern effective mitophagy regulation in I/R injury. For instance, nanomedicine delivery systems responsive to microenvironmental cues, such as reactive oxygen species (ROS), pH, enzymatic activity, local microthrombosis, and organ-specific homing peptides [26], [27], [28], [29], can be constructed to enable selective drug release at specific sites and times, thereby achieving precise modulation within ischemic and hypoxic lesions.
Moreover, nanocarriers designed for mitochondrial targeting can efficiently deliver drugs to mitochondria for quality control [30]. This approach not only enables integrated monitoring and therapeutic effects [31], [32] but also significantly enhances the efficacy of selective mitophagy intervention and mitochondrial function preservation. In addition to precise delivery of drugs [33], [34], [35] and therapeutic molecules [36], [37], [38], nanomedicine further enables optimization of mitophagy intervention timing and dosage via real-time dynamic monitoring enabled using nanoprobes [39], [40]. This capability ensures that both activation and inhibition of mitophagy can be tuned to operate with maximal efficacy within the desired therapeutic window. The combination of nanomedicine strategies with mitophagy regulation thus represents a promising strategy for controlling mitophagy, preserving mitochondrial function, and ultimately mitigating multi-organ I/R injury.
In this review, we comprehensively summarize and discuss recent advances and emerging opportunities in mitophagy research within the context of I/R diseases. We first discuss the latest advances in mitophagy mechanisms related to I/R injury, including the initial effects of the I/R environment on autophagy, particularly mitophagy, in critical organs such as the brain, heart, liver, and kidneys, as well as the current research status of mitophagy regulation in these organs. We then focus on the rational design of nanomaterials and their potential to regulate mitophagy activity, summarizing the promise of nanomedicine in precisely intervening in mitophagy within the I/R microenvironment and in monitoring mitophagy (Fig. 1). In addition, this review highlights current challenges and future directions in this field, with particular emphasis on the clinical translation potential of nanomedicine-based strategies. It outlines the major barriers to translation and the key considerations for clinical application, and further proposes that future research prioritize the development of individualized, scalable, controllable, and safe translatable strategies. Such efforts are essential to advance precise interventions for I/R injury and to establish new paradigms in precision medicine.