Targeting DNA to endoplasmic reticulum efficiently enhances gene delivery and therapy

Gene-therapy mediated by non-viral carriers is gaining an increasing popularity due to its high biosafety and the convenience of production with large scale, yet inefficient gene delivery is a limiting obstacle. Few gene vectors can avoid the endosome-lysosome route, and as a result, their DNA payloads are easily decomposed during transfection. Herein, a peptide (pardaxin, PAR)-modified cationic liposome (PAR-Lipo) targeting to endoplasmic reticulum (ER) was developed for improving gene delivery efficiency. Interestingly, compared to non-PAR-modified cationic liposomes (Non-Lipos) and Lipofectamine 2000 (Lipo 2000, a commercial genetic vector), PAR-Lipos mediated remarkably higher gene delivery efficiency in vitro and better antitumor efficacy in vivo. It was demonstrated that PAR-Lipos could be accumulated into the ER via a non-lysosome intracellular route after cellular internalization, which induced a retaining of DNA payload in the ER close to the nucleus, while Non-Lipos, like most conventional cationic carriers, mainly presented a lysosomal retention after their endocytosis. The unique intracellular transport behavior of PAR-Lipos can enhance the protection to DNA payload, prolong their residence time in the cell, and promote their entry into the nucleus relying on the intimate relationship between ER and nuclear membrane, which is the explanation for enhanced gene-therapy effect mediated by PAR-Lipos. Our research may provide alternative means of efficiently delivering genes in cells.