Virus-esque nucleus-targeting nanoparticles deliver trojan plasmid for release of anti-tumor shuttle protein

Abstract Gene therapy has gathered vast interest and been proved promising and prospective. While gene therapy evolves fast, demands of high transfecting efficiency and less toxic gene vectors are not sufficiently fulfilled. The progression of materials is doing the favor from which therapeutic application benefited is helping reshape treatments of cancer. In this work, we synthesized fluorinated branched polyethylenimine (PF) and RGD-R8-PEG-HA (RRPH). When mixed with plasmids, the PF33 could form a compact nanoparticle PFC (Fluorinated PEI/plasmid Complex) and showed high transfection efficiency (>70% in A549 cells). Peptide modification and PEGylation on HA constituted the RRPH, and coating on the PFC would enable the ultimate nanoparticle RRPHC (RRPH coating PFC Complex) achieve long-term circulation and tumor tissue-penetration while maintaining the high transfection efficiency of PFC. Observations about the behavior in cellular organisms of RRPHC revealed its nucleus-targeting tendency. The in vivo distribution images revealed the RRPHC nanoparticles, compared to HAC (HA coated PFC, used as control) could achieve extended accumulation specifically on tumor regions rather than stay in other organs. While loaded with plasmids encoding our rationally designed trojan Apoptin (pSTA), RRPHC could establish compounds for the massive production of membrane-penetrating protein. Hence these cancer-killing proteins would charge at nucleus once phosphorylated and finish the task of destruction. Both in vitro and in vivo treatment using RRPHC/pSTA nanoparticles resulted in remarkable tumor suppression and the cytotoxicity tests demonstrated its low toxicity. In summary, pSTA encapsulating RRPHC nanoparticles may have potential applications in cancer gene therapy.