CXCR4-Functionalized Biomimetic Nanoparticles Enable ROS-Triggered Hesperetin Release for Acute Lung Injury Therapy

Abstract

Objective Acute lung injury (ALI) features uncontrolled pulmonary inflammation and excessive reactive oxygen species (ROS), lacking effective targeted therapies. Hesperetin (HST) has anti-inflammatory and antioxidant effects, but poor solubility and weak lesion targeting limit its application. Herein, based on the characteristics of ALI lesion stromal cell-derived factor-1α (SDF-1α) and ROS overexpression, the authors constructed ROS-sensitive oxy-hydroxypropyl-β-cyclodextrin (Oxi-Hp-β-CD) and CXCR4-modified biomimetic nanoparticles (CXCR4-HST@BNPs) to achieve targeted (CXCR4/SDF-1α axis) and ROS-triggered HST delivery for the treatment of ALI. Methods MLE-12 cells with overexpressed CXCR4 were constructed by lentiviral transduction and the cell membranes were extracted for encapsulating nanoparticles loaded with HST. Physicochemical properties, drug release profile, cellular uptake and in vivo distribution were characterized, and therapeutic efficacy and mechanisms were assessed using LPS-induced cellular and murine ALI models. Results Prepared CXCR4-HST@BNPs possessed uniform particle size, high encapsulation efficiency and obvious ROS-dependent drug release. Benefiting from CXCR4/SDF-1α-mediated active targeting, the nanoparticles selectively accumulated in inflamed lung tissue with favorable acute biocompatibility. In vitro and in vivo experiments confirmed that CXCR4-HST@BNPs significantly alleviated pulmonary edema, suppressed pro-inflammatory cytokine overexpression and alleviated inflammatory injury. Mechanistically, the formulation eliminated excessive intracellular ROS, restored mitochondrial membrane potential and raised cellular ATP levels. Conclusion In conclusion, CXCR4-HST@BNPs effectively ameliorate ALI via anti-oxidation and mitochondrial protection, representing a prospective ALI-targeted nanotherapeutic candidate.