Clinically, ischemic ailments symbolize a number one trigger of world mortality and incapacity, affecting very important organs together with the center, mind, liver, and kidneys [1], [2], [3], [4]. Though reperfusion is indispensable for tissue survival after ischemia, it steadily precipitates secondary damage cascades characterised by oxidative stress [5], [6], calcium overload [7], [8], inflammatory responses [9], [10], [11], and apoptosis [12], [13], [14], thereby driving mobile damage and poor prognosis [15], [16]. Accordingly, in myocardial infarction (MI), acute ischemic stroke (AIS), acute kidney damage (AKI), liver transplantation, and spinal wire ischemia, I/R damage stays a significant determinant of organ dysfunction and mortality [17], [18], [19]. However, the inherent complexity and unpredictable nature of I/R damage proceed to pose formidable challenges for its efficient prevention and therapy.
Mitochondrial dysfunction has emerged as a essential mechanism in I/R damage, driving cell loss of life by means of a number of pathological pathways [20], [21]. Consequently, defending mitochondrial perform represents a promising therapeutic technique to mitigate I/R damage. In response to mitochondrial impairment, cells activate mitophagy, a selective type of autophagy that targets and removes broken mitochondria. As an adaptive mitochondrial high quality management mechanism, mitophagy performs a central position in sustaining mitochondrial homeostasis and power metabolism [22], [23]. Nonetheless, mitophagy is just not all the time helpful. When it’s appropriately activated and matched with intact autophagic flux, it facilitates the clearance of dysfunctional mitochondria. In distinction, dysregulated or extreme activation might result in mitochondrial depletion and power failure, which in flip exacerbates cell loss of life and tissue damage [24], [25]. These options render the depth, timing, and autophagic flux competence of mitophagy essential concerns for therapeutic intervention.
As a result of excessive complexity of the lesion microenvironment and the heterogeneity of spatiotemporal regulation of mitophagy. Exactly controlling the depth and timing of mitophagy to realize optimum tissue safety stays a essential problem. On this context, the speedy growth of nanomedicine has offered not solely progressive approaches for exact mitophagy modulation, but additionally a conceptual framework for addressing the spatiotemporal constraints that govern efficient mitophagy regulation in I/R damage. As an example, nanomedicine supply programs aware of microenvironmental cues, resembling reactive oxygen species (ROS), pH, enzymatic exercise, native microthrombosis, and organ-specific homing peptides [26], [27], [28], [29], might be constructed to allow selective drug launch at particular websites and occasions, thereby attaining exact modulation inside ischemic and hypoxic lesions.
Furthermore, nanocarriers designed for mitochondrial focusing on can effectively ship medicine to mitochondria for high quality management [30]. This method not solely allows built-in monitoring and therapeutic results [31], [32] but additionally considerably enhances the efficacy of selective mitophagy intervention and mitochondrial perform preservation. Along with exact supply of medication [33], [34], [35] and therapeutic molecules [36], [37], [38], nanomedicine additional allows optimization of mitophagy intervention timing and dosage by way of real-time dynamic monitoring enabled utilizing nanoprobes [39], [40]. This functionality ensures that each activation and inhibition of mitophagy might be tuned to function with maximal efficacy throughout the desired therapeutic window. The mix of nanomedicine methods with mitophagy regulation thus represents a promising technique for controlling mitophagy, preserving mitochondrial perform, and in the end mitigating multi-organ I/R damage.
On this assessment, we comprehensively summarize and focus on current advances and rising alternatives in mitophagy analysis throughout the context of I/R ailments. We first focus on the newest advances in mitophagy mechanisms associated to I/R damage, together with the preliminary results of the I/R surroundings on autophagy, notably mitophagy, in essential organs such because the mind, coronary heart, liver, and kidneys, in addition to the present analysis standing of mitophagy regulation in these organs. We then give attention to the rational design of nanomaterials and their potential to control mitophagy exercise, summarizing the promise of nanomedicine in exactly intervening in mitophagy throughout the I/R microenvironment and in monitoring mitophagy (Fig. 1). As well as, this assessment highlights present challenges and future instructions on this discipline, with explicit emphasis on the scientific translation potential of nanomedicine-based methods. It outlines the main boundaries to translation and the important thing concerns for scientific software, and additional proposes that future analysis prioritize the event of individualized, scalable, controllable, and secure translatable methods. Such efforts are important to advance exact interventions for I/R damage and to ascertain new paradigms in precision medication.
