The rapid development of CRISPR/Cas9 systems has opened up tantalizing prospects to sensitize cancers to chemotherapy using efficient targeted genome editing, but safety concerns and possible off-target effects of viral vectors remain a major obstacle for clinical application. Thus, the construction of novel nonviral tumor-targeting nanodelivery systems has great potential for the safe application of CRISPR/Cas9 systems for gene–chemo-combination therapy. Here, we report a polyamidoamine-aptamer-coated hollow mesoporous silica nanoparticle for the co-delivery of sorafenib and CRISPR/Cas9. The core–shell nanoparticles had good stability, enabled ultrahigh drug loading, targeted delivery, and controlled-release of the gene–drug combination. The nanocomplex showed >60% EGFR-editing efficiency without off-target effects in all nine similar sites, regulating the EGFR-PI3K-Akt pathway to inhibit angiogenesis, and exhibited a synergistic effect on cell proliferation. Importantly, the co-delivery nanosystem achieved efficient EGFR gene therapy and caused 85% tumor inhibition in a mouse model. Furthermore, the nanocomplex showed high accumulation at the tumor site in vivo and exhibited good safety with no damage to major organs. Due to these properties, the nanocomplex provides a versatile delivery approach for efficient co-loading of gene–drug combinations, allowing for precise gene editing and synergistic inhibition of tumor growth without apparent side effects on normal tissues.

Although it has been demonstrated that rareearth elements (REEs) disturb and alter the catalytic activity of numerous natural enzymes, their effects on nanomaterialbased artificial enzymes (nanozymes) have been seldom explored. In this work, the influence of REEs on the peroxidase-like activity of bare gold nanoparticles (GNPs) is investigated for the first time, and a new type of Ce 3+ -activated peroxidase mimetic activity of GNPs is obtained. The introduced Ce 3+ can be bound to the bare GNP surface rapidly through electrostatic attraction, after which it donates its electron to the bare GNP. As H 2 O 2 is a good electron scavenger, more • OH radicals are generated on the surfaces of the bare GNPs, which can considerably enhance TMB oxidation. Due to its redox cycling ability, the activation effect of Ce 3+ is proved to be more efficient in comparison to those of the other reported metal ion activators (e.g., Bi 3+ , Hg 2+ , and Pb 2+ ). In addition, it is determined that Ce 3+ should directly contact with the gold core to trigger its activation effect. When the surface states of the bare GNPs are altered, the Ce 3+ -stimulated effect is strongly inhibited. Furthermore, a novel colorimetric method for Ce 3+ is developed, on the basis of its enhancing effect on the peroxidase mimetic activity of bare GNPs. The sensitivity of this newly developed method for Ce 3+ is excellent with a limit of detection as low as 2.2 nM. This study not only provides an effective GNP-based peroxidase mimic but also contributes in realizing new applications for nanozymes.

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Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery. However, the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application. Herein, a novel “core‒shell” co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid (UA) and polyphenol (EGCG) with the EpCAM-aptamer modification for hepatocellular carcinoma (HCC) synergistic treatment. As the nature products derived from food-plant, UA and EGCG had good anticancer activities and low toxicity. With the simple and “green” method, the nanodrugs had the advantages of good stability, pH-responsive and strong penetration of tumor tissues, which was expected to increase tumor cellular uptake, long circulation and effectively avoid the potential defects of traditional carriers. The nanocomplex exhibited the low cytotoxicity in the normal cells in vitro, good biosafety of organic tissues and efficient tumor accumulation in vivo . Importantly, UA combined with EGCG showed the immunotherapy by activating the innate immunity and acquired immunity resulting in significant synergistic therapeutic effect. The research could provide new ideas for the research and development of self-assembly delivery system in the future, and offer effective intervention strategies for clinical HCC treatment.

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