Co-delivery of TRAIL DNA and salinomycin for cancer therapy <i>via</i> enhanced apoptosis and cancer stemness inhibition

Cancer treatment faces challenges including drug resistance to intrinsic apoptosis pathways and the persistence of cancer stem cells (CSCs). The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces extrinsic apoptosis in tumor cells by binding to death receptors while sparing normal cells. TRAIL-based gene therapy has emerged as a promising solution to address the short half-life limitation of recombinant TRAIL proteins. To further enhance the therapeutic efficacy, combination strategies with TRAIL sensitizer salinomycin (Sali) appear to be particularly effective. Sali not only upregulates death receptor expression and reactive oxygen species (ROS) levels but also modulates CSC-related gene expression, contributing to its multifaceted antitumor activity. In this study, a micelle system was developed for co-delivery of TRAIL plasmids (pTRAIL) and Sali to tumor sites. γ-Polyglutamic acid (γ-PGA)-coating improved the <i>in vivo</i> stability profile of the co-delivery nanocomposites. The resulting co-delivery system (γ-PGA/Sali@P-S/pTRAIL) effectively induced apoptosis and suppressed CSC-associated gene expression in cervical cancer cells. Both <i>in vitro</i> and <i>in vivo</i> evaluations demonstrated the system's potent antitumor efficacy, highlighting its potential as a promising strategy for cervical cancer therapy.