Since conventional chemotherapy is a systemic treatment that affects the body globally and will not concentrate inside the tumor, it causes adverse side effects to patients. In this study, doxorubicin (DOX) together with solid gold nanoparticles (GNPs) or hollow gold nanoparticles (HGNPs), respectively, is loaded inside thermosensitive liposomes (GNPs&DOX-TLs and HGNPs&DOX-TLs), where the GNPs and HGNPs act as a “nanoswitch” for killing tumor cells directly by hyperthermia and triggering DOX release from TLs in the tumor quickly by near infrared laser (NIR) illumination. In addition, this study investigated the photothermal transformation ability, NIR triggered drug release behavior, and the intracellular uptake and cytotoxicity of breast tumor cells and the thermo-chemotherapy mediated by the co-delivery of GNPs&DOX-TLs and HGNPs&DOX-TLs. GNPs and HGNPs had very different light-to-heat transduction efficiencies, while the hollow HGNPs had the advantage of NIR surface plasmon tunability, resulting in the photothermal ablation of tumors with 800 nm light penetration in tissue. The prepared HGNPs&DOX-TLs exhibited a spherical shape with a diameter of 190 nm and a ξ potential of −29 mV, which were steadily dispersed for at least one month. The co-encapsulated DOX was released under hyperthermia caused by NIR-responsive HGNPs and the local drug concentration increased along with the disintegration of the liposomal membrane. This co-delivery of HGNPs&DOX-TLs produced a synergistic cytotoxicity response, thereby enhancing anticancer efficacy 8-fold and increasing the survival time compared to GNPs&DOX-TLs. This work suggested that the co-delivery of HGNPs&DOX-TLs followed by burst-release of DOX using NIR-responsive HGNPs sensitized cancer cells to the chemotherapeutic compound, which provided a novel concept for the combination strategy of chemotherapy and photothermal therapy. These results suggest that the markedly improved therapeutic efficacy and decreased systemic toxicity of the NPs presented in this study hold significant potential for future cancer treatment.

Cationic polymers are a class of promising carriers for nucleic acid delivery. However, the balance between biosafety and transfection efficiency is still a major obstacle for nucleic acid delivery. Accurate structural design can effectively evaluate the relationship between structural factors and nucleic acid delivery. Previously designed series of vectors optimized based on artificial amino acid Stp have been shown to effectively improve gene transfection. Here, a series of sequenced-defined oligomers containing hydrophobic oleic acid with different topologies, different charge densities and with or without crosslinking cystine domains were designed and synthesized for a better understanding of the structure–activity relationship. The oligomers were further mixed with either pDNA or siRNA to form polyplexes. The particle size, zeta potential, formation properties, in vitro stability and reductive responsiveness of the polyplexes were investigated. In addition, studies regarding the transfection efficiency, cellular uptake, cellular trafficking, cytotoxicity and hemolysis were performed. The resulting oligomers display general good complexation ability with pDNA and siRNA with enhanced stability and redox sensitivity. Some of the oligomers showed adequate or surpassed transfection efficiency compared with PEI. The polyplexes formed with oligomer #1 have good cellular uptake and endo-lysosome escape properties. In addition, all the oligomers and the polyplexes showed low cytotoxicity and hemolysis, and demonstrated high biocompatibility. In summary, the results evidenced that tuning the charge density combined with hydrophobic oleic acid and thiol crosslinking cystine improves the overall performance in delivering pDNA and siRNA.