Multistage-Responsive Gene Editing to Sensitize Ion-Interference Enhanced Carbon Monoxide Gas Therapy.

As a promising therapeutic modality targeting cancer, gas therapy still faces critical challenges, especially in enhancing therapeutic efficacy and avoiding gas poisoning risks. Here, a pH/glutathione (GSH) dual stimuli-responsive CRISPR/Cas9 gene-editing nanoplatform combined with calcium-enhanced CO gas therapy for precise anticancer therapy, is established. In the tumor microenvironment (TME), the fast biodegradation of the CaCO3 layer via pH-induced hydrolyzation allows glucose oxidase (GOx) to catalyze glucose for H2 O2 production, which further reacts with manganese carbonyl (MnCO) and achieves the precise release of CO gas. Simultaneously, in situ Ca2+ overload from CaCO3 degradation disturbs mitochondrial Ca2+ homeostasis, resulting in Ca2+ -driven reactive oxygen species (ROS) formation and subsequent mitochondrial apoptosis signaling pathway activation. Subsequently, by GSH-induced cleavage of a disulfide bond, the released Cas9/sgRNA (RNP) can achieve nuclear factor E2-related factor 2 (Nrf2) gene ablation to sensitize gas therapy by interfering with ROS signaling. This therapeutic modality endows codelivery of CRISPR, ions, and gas with smart control features, which demonstrates great potential for future clinical applications in precise nanomedicine.

DNAzyme-Assisted Nano-Herb Delivery System for Multiple Tumor Immune Activation.

As a promising therapeutic strategy against cancer, immunotherapy faces critical challenges, especially in solid tumors. Immune checkpoint blockade therapy, particularly blocking the interaction of the programmed cell death 1 (PD1)-PD1 ligand 1 (PD-L1) axis, can reverse the suppression of T cells so as to destroy tumor cells and exert antitumor effects. Here, a strategy of multiple activation of immune pathways is developed, to provide supporting evidence for potential antitumor therapies. Briefly, a pH/glutathione responsive drug-loading hollow-manganese dioxide (H-MnO2 )-based chlorine6 (Ce6)-modified DNAzyme therapeutic nanosystem for the combination of gene therapy and immunotherapy is established. The H-MnO2 nanoparticles could efficiently deliver the DNAzyme and glycyrrhizic acid (GA) to enhance the tumor target effects. In the tumor microenvironments, the biodegradation of H-MnO2 via pH-induced hydrolyzation allows the release of guest DNAzyme payloads and host Mn2+ ions, which serve as PD-L1 mRNA-targeting reagent and require DNAzyme cofactors for activating gene therapy. In addition, Mn2+ is also associated with the immune activation of thcGAS-STING pathway. Auxiliary photosensitizers Ce6 and GA could produce reactive oxygen species, resulting in immunogenic cell death. Overall, this study provides a general strategy for targeted gene inhibition and GA release, which is valuable for the development of potential tumor immunotherapies.

Erratum: Author correction to "Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy" [Acta Pharm Sin B (2022) 4224-4234].

[This corrects the article DOI: 10.1016/j.apsb.2022.06.016.].

Plasmonic-driven charge separation through combining Ag nanoparticles (Ag NPs) to form a double Z-scheme heterostructure in WO3/BiOCl/g-C3N4 for the photocatalytic degradation of antibiotics.

Integrating a heterojunction system with the impact of surface plasmon resonance (SPR) is an executable and innovative tactic for photocatalyst amelioration. Ag nanoparticle (Ag NP)-modified WO3/BiOCl/g-C3N4 (WB-CN) was favorably fabricated through in situ photo deposition assembly to form double heterojunctions (A-WBCN). The degradation performance of A-WBCN is better than that of pure g-C3N4 (CN) and WO3/BiOCl (WB), it can degrade more than 90% of OFLX within 20 minutes, due to Ag NPs performing as a bridge for electron mediators, apart from the implications of SPR in A-WBCN. The results of UV diffuse reflectance spectroscopy indicate that loading with Ag NPs can expand the light absorption range of WB-CN to near-infrared. The photoluminescence spectra and transient photocurrent spectra indicate that Ag NP loading significantly improves the separation efficiency of photogenerated carriers. Density functional theory (DFT) simulation results show that the introduction of Ag NPs can change the direction of carrier movement, resulting in bending of the energy bands of WB and CN, improving the redox ability of A-WBCN, and improving its photocatalytic efficiency. In addition, the intermediate products of OFLX was determined by HPLC-MS analysis. The spin electron resonance (ESR) results indicate that ˙O2- and ˙OH are the main active species in photocatalytic degradation. This work furnishes a fresh idea for upgrading photocatalytic performance and advancing electron transfer.

Intelligent nanotherapeutic strategies for the delivery of CRISPR system.

CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized the development of biomedical research at an unexpected speed in recent years. The development of intelligent and precise CRISPR delivery strategies in a controllable and safe manner is the prerequisite for translational clinical medicine in gene therapy field. In this review, the therapeutic application of CRISPR delivery and the translational potential of gene editing was firstly discussed. Critical obstacles for the delivery of CRISPR system in vivo and shortcomings of CRISPR system itself were also analyzed. Given that intelligent nanoparticles have demonstrated great potential on the delivery of CRISPR system, here we mainly focused on stimuli-responsive nanocarriers. We also summarized various strategies for CIRSPR-Cas9 system delivered by intelligent nanocarriers which would respond to different endogenous and exogenous signal stimulus. Moreover, new genome editors mediated by nanotherapeutic vectors for gene therapy were also discussed. Finally, we discussed future prospects of genome editing for existing nanocarriers in clinical settings.

Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy.

Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO2-x ) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO2-x to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90α (HSP90α), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO2-x demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.