Intracellular delivery of therapeutic biomacromolecules, including nucleic acids and proteins, attracts extensive attention in biotherapeutics for various diseases. Herein, a strategy is proposed for the construction of poly(disulfide)s for the efficient delivery of both nucleic acids and proteins into cells. A convenient photo-cross-linking polymerization was adopted between disulfide bonds in two modified lipoic acid monomers (Zn coordinated with dipicolylamine analogue (ZnDPA) and guanidine (GUA)). The disulfide-containing main chain of the resulting poly(disulfide)s was responsive to reducing circumstance, facilitating the release of cargos. By screening the feeding ratio of ZnDPA and GUA, the resulting poly(disulfide)s exhibited better performance in the delivery of nucleic acids including plasmid DNA and siRNA than commercially available transfection reagents. Cellular uptake results revealed that the polymer/cargo complexes entered the cells mainly following a thiolmediated uptake pathway. Meanwhile, the polymer could also efficiently deliver proteins into cells without an obvious loss of protein activity, showing the versatility of the poly(disulfide)s for the delivery of various biomacromolecules. Moreover, the in vivo therapeutic effect of the materials was verified in the E.G7-OVA tumor-bearing mice. Ovalbumin-based nanovaccine induced a strong cellular immune response, especially cytotoxic T lymphocyte cellular immune response, and inhibited tumor growth. These results revealed the promise of the poly(disulfide)s in the application of both gene therapy and immunotherapy.

Photodynamic therapy occupies an important position in cancer therapy because of its minimal invasiveness and high spatiotemporal precision, and photodynamic/gene combined therapy is a promising strategy for additive therapeutic effects. However, the asynchronism and heterogeneity between traditional chemical photosensitizers and nucleic acid would restrict the feasibility of this strategy. KillerRed protein, as an endogenous photosensitizer, could be directly expressed and take effect in situ by transfecting KillerRed reporter genes into cells. Herein, a simple and easily prepared sodium alginate (SA)-doping cationic nanoparticle SA@GP/DNA was developed for dual gene delivery. The nanoparticles could be formed through electrostatic interaction among sodium alginate, polycation, and plasmid DNA. The title complex SA@GP/DNA showed good biocompatibility and gene transfection efficiency. Mechanism studies revealed that SA doping could facilitate the cellular uptake and DNA release. Furthermore, SA@GP/DNA was applied to the codelivery of p53 and KillerRed reporter genes for the synergistic effect combining p53-mediated apoptosis therapy and KillerRed-mediated photodynamic therapy. The ROS generation, tumor cell growth inhibition, and apoptosis assays proved that the dual-gene transfection could mediate the better effect compared with single therapy. This rationally designed dual gene codelivery nanoparticle provides an effective and promising platform for genetically bimodal therapy.

The combined chemo-gene therapy has become a promising approach for enhanced anti-cancer treatment. However, effective co-delivery of therapeutic gene and drug into target cells and tissues remains a major obstacle....