Therapeutic systems to induce reactive oxygen species (ROS) have received tremendous success in the research of tumor theranostics, but suffered daunting challenges in limited efficacy originating from low presence of reactants and reaction kinetics within cancer cells. Here, ferrous sulfide‐embedded bovine serum albumin (FeS@BSA) nanoclusters, in an amorphous nature, are designed and synthesized via a self‐assembly approach. In acidic conditions, the nanoclusters degrade and simultaneously release H2S gas and Fe2+ ions. The in vitro study using Huh7 cancer cells reveals that Fe2+ released from FeS@BSA nanoclusters induces the toxic hydroxyl radical (·OH) effectively via the Fenton reaction. More interestingly, H2S gas released intracellularly presents the specific suppression effect to catalase activity of cancer cells, resulting in the promoted presence of H2O2 that facilitates the Fenton reaction of Fe2+ and consequently promotes ROS induction within the cells remarkably. After intravenous administration, the nanoclusters accumulate in the tumors of mice via the enhanced permeability and retention effect and present strong magnetic resonance imaging (MRI) signals. The findings confirm this therapeutic system can enable superior anti‐tumor performance with MRI guidance and negligible side effects. This study, therefore, offers an alternative gas‐amplified ROS‐based therapeutic platform for synergetic tumor treatment.

Immunotherapy has received widespread attention in the treatment of HCC, among which the immune checkpoint inhibitors, such as PD-1 antibodies, have shown promising antitumor effects in phase I/ II clinical trials for advanced therapy in HCC. [3,4] However, the responsiveness to immune checkpoint inhibitors among patients is limited (≈20-30%). Neither nivolumab nor pembrolizumab reached the primary end points of overall survival, which did not achieve the statistical significance, in the randomized phase III trials for advanced HCC patients. [5] Therefore, how to enhance the responsiveness to immunotherapy in HCC patients is a key issue to be addressed urgently.Activation of cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase/interferon gene stimulator (cGAS/STING) signals to upregulate innate immunity has become an emerging strategy for enhancing tumor immunotherapy. cGAS in tumor cells can sense intracellular damaged DNA and activate STING to upregulate type I interferon (IFN) and proinflammatory cytokines, thus inhibiting tumor progression. [6] Crosstalk between tumors and neighboring immune cells can also be achieved by the cGAS/ STING pathway. Tumor DNA can activate cGAS/STING signals Although immunotherapy such as immune checkpoint inhibitors has shown promising efficacy in cancer treatment, the responsiveness among patients is relatively limited. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity has become an emerging strategy for enhancing tumor immunotherapy. Herein, ZnS@BSA (bovine serum albumin) nanoclusters synthesized via a self-assembly approach are reported, where the released zinc ions under acidic tumor microenvironment significantly enhance cGAS/STING signals. Meanwhile, intracellular zinc ions can produce reactive oxygen species, which is further facilitated by the generated H 2 S gas from ZnS@BSA via specifically inhibiting catalase in hepatocellular carcinoma cells. It is found that the nanoclusters activate the cGAS/ STING signals in mice, which promotes the infiltration of CD8 + T cells at the tumor site and cross-presentation of dendritic cells, leading to an improved immunotherapy efficacy against hepatocellular carcinoma.

Cancer Therapy In article number 2104037, Xiang Li, Zhen Gu, Xiujun Cai, and co‐workers report that the generated H2S and released zinc ions from ZnS@BSA nanoclusters promote accumulation of reactive oxygen species to activate cGAS/STING signals in tumor cells. ZnS@BSA nanoclusters are further demonstrated to facilitate antitumor immunotherapy by immune cell infiltration, showing potential for clinical translation.

Nanoparticles are now commonly used as non-viral gene vectors for RNA interference (RNAi) in cancer therapy but suffer from low targeting efficiency in situ. Meanwhile, localized drug delivery systems do not offer the effective capability for intracellular gene transportation. We describe here the design and synthesis of a localized therapeutic system, consisting of gold nanorods (Au NRs) loaded with hTERT siRNA assembled on the surface of ZnGa2O4:Cr (ZGOC) nanofibers. This composite system offers the potential for a LED-induced mild photothermal effect which enhances the phagocytosis of Au NRs carrying siRNA and the subsequent release of siRNA in the cytoplasm. Both phenomena amplify the gene silencing effect and consequently offer the potential for a superior therapeutic outcome.

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