The ubiquitin ligase RNF8 promotes the DNA damage response (DDR). We observed that the expression of RNF8 was increased in bladder cancer cells and that this change in RNF8 expression could be reversed by adenovirus-mediated shRNA treatment. Moreover, we found that RNF8 knockdown sensitized bladder cancer cells to radiotherapy, as demonstrated by reduced cell survival. Additionally, the absence of RNF8 induced a high rate of apoptosis and impaired double-strand break repair signaling after radiotherapy. Furthermore, experiments on nude mice showed that combining shRNF8 treatment with radiotherapy suppressed implanted bladder tumor growth and enhanced apoptotic cell death in vivo. Altogether, our results indicated that RNF8 might be a novel target for bladder cancer treatment.

Sonodynamic therapy (SDT) has gained widespread attention owning to its much deeper tissue penetration depth compared with phototherapy. However, developing sonosensitizers with high sonosensitization efficacy in a tumor hypoxic environment is still a significant challenge. Herein, we fabricated a poly­(amino acid) coordination nanoparticle (PFHF) as a potent sonosensitizer with great biocompatibility and high hydroxyl radical (•OH)-generation capacity for efficient SDT. PFHF was identified as a hexa-coordination structure by X-ray absorption fine structure and density functional theory. Furthermore, PFHF could be excited by ultrasound, which directly cleaved H2O into •OH, achieving oxygen-independent SDT. In addition, doxorubicin-loaded PFHF achieved a significant synergistic chemo-sonodynamic therapeutic effect with a tumor inhibition rate of 89%. The poly­(amino acid) coordination nanoparticle with good biocompatibility and oxygen-independent ability could provide an idea for the rational design of sonosensitizers.

Gold nanoparticles (Au NPs) used as photosensitizers for photothermal therapy (PTT) have attracted extensive attention. However, limited tissue penetration of light seriously hinders the practical application, causing Au NPs to be combined with multiple theranostic agents to improve the treatment effect. Herein, we fabricate one potent gold nanostars (GNS) that can unify the dual nanozyme activities and photothermal property, achieving effective synergistic cascade catalytic and photothermal therapy. Notably, GNS is prepared by a green and facile one-step synthesis method using biodegradable poly­(γ-glutamic acid) as a medium. The single GNS exhibits inherent dual nanozyme activities, glucose oxidase- and peroxidase-like activities, which not only convert glucose of tumor tissue into hydrogen peroxide (H2O2) but also catalyze H2O2 to produce the amount of toxic hydroxyl radicals (•OH), leading to an amplified cascade catalytic therapy. Moreover, the cascade catalytic activity of GNS is enhanced 1.4-fold in the photothermal effect. Finally, the GNS can achieve photoacoustic imaging-guided efficient synergistic cascade catalytic and photothermal therapy with a high antitumor rate of 97.0%. This simple but multifunctional GNS could provide a new strategy facilitating the practical treatment application of single Au NPs.

Adenovirus-mediated gene therapy is a promising strategy for bladder cancer treatment. However, the loss of the coxsackie and adenovirus receptor (CAR) in bladder cancer cells decreases the infection efficiency of the therapeutic adenovirus. In this study, we constructed an Arg-Gly-Asp (RGD)-modified adenovirus, RGDAd-UPII-TK, that carries a suicide gene called HSV-TK that is driven by a human UPII promoter. Then, we tested the bladder cancer specificity of the UPII promotor and the expression of the HSV-TK protein. Additionally, we observed a potent cytotoxic effects of RGDAd-UPII-TK and ganciclovir (GCV) on bladder cancer as demonstrated by reduced cell survival and morphology changes in vitro. Furthermore, we confirmed that RGDAd-UPII-TK in combination with a GCV injection could significantly reduce the established T24 tumor growth and increase apoptosis in vivo. Altogether, our results indicated that the recombinant adenovirus RGDAd-UPII-TK could target bladder cancer through valid gene therapy.