Platelet-Mitochondria Dual-Targeted Nanocarriers for Enhanced Empagliflozin Therapy in Atherosclerosis

Yue Tang¹Tian Yue²Yi Wang³Xue Mei¹Lijun Luo¹Fan Zhang¹Xiaojin Gao¹Yihua Wang¹Jun Hou^2*Chunyang Zhou^1*

• ¹North Sichuan Medical College, Nanchong, China
• ²Chengdu Third People's Hospital, Chengdu, China
• ³Southwest Jiaotong University, Chengdu, China

Atherosclerosis (AS) is a primary cause of cardiovascular disease and significantly contributes to the global disease burden. Empagliflozin (EMP), a candidate drug for AS treatment, has not been clinically approved due to challenges including poor solubility, low bioavailability, and potential toxicity. This study constructed a platelet membrane-biomimetic, mitochondria-targeted delivery system (PM@EPPT) to optimize EMP delivery and evaluate its efficacy against AS. The system was developed by loading EMP into PEG-PCL polymeric micelle, modifying the PEG terminus with triphenylphosphine (TPP), and coating the nanoparticle surface with platelet membranes. PM@EPPT exhibited favorable physical properties and biocompatibility.In vitro experiments demonstrated that this system alleviated oxidative stress-induced macrophage apoptosis by scavenging reactive oxygen species (ROS), restoring mitochondrial membrane potential, and activating mitophagy. In ApoE -/-mouse models, PM@EPPT reduced aortic plaque area by 43%, decreased expression of inflammatory markers (CD68 and MMP-9), increased levels of the plaque stability marker (α-SMA), and improved lipid profiles. In conclusion, PM@EPPT enhances EMP bioavailability through platelet membrane-mediated arterial plaque targeting and TPP-modified mitochondrial targeting. This study provides experimental evidence for optimizing EMP efficacy in AS treatment and developing therapeutic platforms for other poorly soluble drugs targeting AS.