TRAIL-secreting human mesenchymal stem cells engineered by a non-viral vector and photochemical internalization for pancreatic cancer gene therapy

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic protein to selectively induce cancer cell apoptosis. However, TRAIL exhibits low stability and short half-life due to its denaturation. Thus, delivering the TRAIL gene for stem cell-mediated gene therapy was conducted by using non-viral vectors (a less efficient but safer method). To overcome the limitation of non-viral vectors, photochemical internalization (PCI) was utilized for enhanced transfection efficiency of secreting TRAIL from human mesenchymal stem cells (hMSCs). To explore a more effective approach for cancer treatment, polyplexes were formed by using TRAIL plasmid (pTRAIL) and branched polyethyleneimine (bPEI). PCI is applied to improve polyplex entrapping in hMSCs and enhance the transfection efficiency of TRAIL into hMSCs for secretion in tumors via a homing effect. We demonstrate that PCI-mediated polyplex loading significantly enhanced TRAIL expression in stem cells and that homing ability magnified cancer targeting. The xenograft mouse model shows that polyplex loaded hMSCs (pTRAIL/bPEI@hMSCs) under laser irradiation results in a beneficial therapeutic antitumor effect compared to unloaded polyplexes and pTRAIL/bPEI@hMSCs. Taken together, the delivery of PCI-pTRAIL/bPEI@hMSCs offers exciting potential treatments in pancreatic cancer gene therapy via the enhanced the transfection efficiency of TRAIL by PCI system and the tumor homing properties of hMSCs.