Targeting Inflammation-Oxidative Stress Crosstalk: Advances and Challenges in Nanocarrier-Based Interventional...

Pulmonary arterial hypertension (PAH) is a cardiovascular disease characterized by a hidden or insidious onset with symptoms including dyspnea and heart failure, which can result in sudden death. Inflammation and oxidative stress are key factors in the pathogenesis of PAH. Hence, anti-inflammatory and antioxidant agents are promoted as therapeutically beneficial. However, the efficacy and safety of these therapeutics are limited by poor solubility and stability, short half-life, lack of targeting capability, and significant side effects. The pulmonary vasculature of patients with PAH exhibits highly heterogeneous blood flow distribution, characterized by reduced wall shear stress and vortex formation at pulmonary artery bifurcations. Abnormal shear stress impairs endothelial function and induces progressive pulmonary vascular remodeling. Combined with endothelial barrier dysfunction, these hemodynamic alterations collectively govern the adhesion, retention and transmural transport of nanocarriers within diseased blood vessels. Nanocarriers (NCs) including liposomes, polymeric and exosomes, through intelligent responsiveness, combination therapy, and personalized and precision delivery strategies, can significantly enhance drug stability, prolong half-life, achieve specific targeting of pulmonary lesions, and reduce side effects. In addition, local administration methods, such as aerosol inhalation and intratracheal instillation, can achieve efficient drug accumulation in the lungs, thereby reducing systemic toxicity. This review summarizes the latest advances in the application of NCs to deliver anti-inflammatory and antioxidant agents for the treatment of PAH, and sorts out multiple translational bottlenecks identified in preclinical investigations. These critical challenges include rapid pulmonary clearance of inhaled nanoformulations, unclear long-term safety after repeated administration, low scalable production yield of nanocarriers, poor storage stability of preparations, inconsistent drug encapsulation efficiency, and unclarified in vivo action mechanisms. It provides solid theoretical support to address the above translational hurdles and advance precision clinical therapy for PAH.