Lipoic acid-modified epirubicin liposomal system for tumor-targeted drug delivery and cardiotoxicity reduction

This study aimed to address the bottlenecks of low delivery efficiency and high cardiotoxicity of anthracyclines by constructing liposomes of epirubicin functionalized with lipoic acid (Epi Lip@LA). This system was endowed with dual functions of dynamic targeting and microenvironmental response through lipoic acid modification: the lipoic acid group in DSPE-PEG2000-LA enhanced the uptake efficiency of tumor cells through dynamic covalent bond-mediated targeted delivery, and the high concentration of glutathione (GSH) in the tumor microenvironment triggered the specific cleavage of disulfide bonds to achieve precise drug release. Meanwhile, lipoic acid cooperatively blocked myocardial oxidative stress and inflammatory injury by scavenging reactive oxygen species, maintaining mitochondrial membrane potential stability, and inhibiting NLRP3 inflammasome activation. In vivo studies demonstrated that this system significantly enhanced the anti-tumor efficacy while effectively alleviating pathological changes such as myocardial fibrosis, achieving dual optimization of drug delivery efficiency and cardiac safety. This work provides an innovative strategy for developing nanocarrier systems with both efficient tumor targeting and systemic protective functions.