Chitosan Nanoparticles for the Treatment of Ischemia-Reperfusion Injury: Mechanisms, Preclinical Evidence, Challenges, and Future Perspectives

Ischemia-reperfusion injury (IRI) is a complex pathological process involved in conditions such as organ transplantation, trauma, vascular surgery, myocardial infarction, and stroke. Although reperfusion is essential for restoring oxygen and nutrients to ischemic tissues, it can paradoxically worsen tissue damage through oxidative stress, mitochondrial dysfunction, endothelial injury, inflammation, immune-cell infiltration, microvascular dysfunction, and regulated cell death. The multifactorial and rapidly evolving nature of IRI limits the effectiveness of traditional therapeutic approaches. Therefore, there is a strong need for strategies capable of simultaneously targeting multiple pathological pathways. Chitosan nanoparticles have emerged as promising nanocarriers for IRI therapy due to their biocompatibility, biodegradability, low toxicity, and ability to be chemically modified. They can encapsulate diverse therapeutic agents, including antioxidants, anti-inflammatory compounds, proteins, peptides, and nucleic acids, thereby improving drug stability, bioavailability, tissue retention, and enabling controlled or stimuli-responsive release. This review summarizes current knowledge on IRI pathophysiology and highlights the therapeutic mechanisms of chitosan nanoparticles, particularly their effects on oxidative stress, inflammation, mitochondrial dysfunction, endothelial injury, and apoptosis. In addition, recent preclinical studies applying chitosan-based nanocarriers in cerebral, hepatic, renal, cardiac, and intestinal IRI are discussed.