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.].

In-Tumor Biosynthetic Construction of Upconversion Nanomachines for Precise Near-Infrared Phototherapy.

Targeted construction of therapeutic nanoplatforms in tumor cells with specific activation remains appealing but challenging. Here, we design a cancer-motivated upconversion nanomachine (UCNM) based on porous upconversion nanoparticles (p-UCNPs) for precise phototherapy. The nanosystem is equipped with a telomerase substrate (TS) primer and simultaneously encapsulates 5-aminolevulinic acid (5-ALA) and d-arginine (d-Arg). After coating with hyaluronic acid (HA), it can readily get into tumor cells, where 5-ALA induces efficient accumulation of protoporphyrin IX (PpIX) via the inherent biosynthetic pathway, and the overexpressed telomerase prolonged the TS to form G-quadruplexes (G4) for binding the resulting PpIX as a nanomachine. This nanomachine can respond to near-infrared (NIR) light and promote the active singlet oxygen (1O2) production due to the efficiency of Förster resonance energy transfer (FRET) between p-UCNPs and PpIX. Intriguingly, such oxidative stress can oxidize d-Arg into nitric oxide (NO), which relieves the tumor hypoxia and in turn improves the phototherapy effect. This in situ assembly approach significantly enhances targeting in cancer therapy and might be of considerable clinical value.

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.

Controlled CRISPR-Cas9 Ribonucleoprotein Delivery for Sensitized Photothermal Therapy.

Manipulation of CRISPR delivery for stimuli-responsive gene editing is crucial for cancer therapeutics through maximizing efficacy and minimizing side-effects. However, realizing controlled gene editing for synergistic combination therapy remains a key challenge. Here, a near-infrared (NIR) light-triggered thermo-responsive copper sulfide (CuS) multifunctional nanotherapeutic platform is constructed to achieve controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and doxorubicin for tumor synergistic combination therapy involving in gene therapy, mild-photothermal therapy (PTT), and chemotherapy. The semiconductor CuS serves as a "photothermal converter" and can stably convert NIR light (808 nm) into local thermal effect to provide photothermal stimulation. The double-strand formed between CuS nanoparticle-linked DNA fragments and single-guide RNA is employed as a controlled element in response to photothermal stimulation for controlled gene editing and drug release. Hsp90α, one subunit of heat shock protein 90 (Hsp90), is targeted by Cas9 RNP to reduce tumor heat tolerance for enhanced mild-PTT effects (≈43 °C). Significant synergistic therapy efficacy can be observed by twice NIR light irradiation both in vitro and in vivo, compared to PTT alone. Overall, this exogenously controlled method provides a versatile strategy for controlled gene editing and drug release with potentially synergistic combination therapy.

Chylomicrons-Simulating Sustained Drug Release in Mesenteric Lymphatics for the Treatment of Crohn's-Like Colitis.

BACKGROUND AND AIMS: Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn's disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn's colitis. METHODS: We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10-/- spontaneous experimental colitis. RESULTS: ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN. CONCLUSION: Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment.

Mesopore to Macropore Transformation of Metal-Organic Framework for Drug Delivery in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic relapsing autoimmune disease that is characterized by segmental intestinal inflammation. There is an urgent need for more efficient inflammation-targeting strategies to improve therapeutic effect and reduce systemic drug exposure. Herein, an oxidation-responsive metal-organic framework material (Ce-MOF@PSS) is reported that preferentially adheres to inflamed intestine via enema. The overproduced reactive oxygen species (ROS) at inflammatory sites induces transformation of Ce-MOF@PSS from mesopore to macropore with local drug release. In experimental colitis, the Ce-MOF@PSS delivery system exhibits excellent inflammation-targeting efficacy and superior therapeutic effect over free drug on suppressing inflammation and repairing intestinal barrier function. Accordingly, by targeting intestinal inflammation, increasing local drug concentrations, scavenging ROS, reducing systemic exposure, and exhibiting excellent safety profiles, it is considered that the Ce-MOF drug delivery platform can be intensively developed as a translational nanomedicine for the management of IBD and other inflammatory diseases.

Diagnosis and treatment of novel coronavirus pneumonia based on the theory of traditional Chinese medicine.

Since the outbreak of novel coronavirus pneumonia (coronavirus disease 2019, COVID-19), it has rapidly spread to 187 countries, causing serious harm to the health of people and a huge social burden. However, currently, drugs specifically approved for clinical use are not available, except for vaccines against COVID-19 that are being evaluated. Traditional Chinese medicine (TCM) is capable of performing syndrome differentiation and treatment according to the clinical manifestations of patients, and has a better ability of epidemic prevention and control. The authors comprehensively analyzed the etiology and pathogenesis of COVID-19 based on the theory of TCM, and discussed its syndrome differentiation, treatment and prevention measures so as to provide strategies and reference for the prevention and treatment with TCM.

Coreopsis Tinctoria Modulates Lipid Metabolism by Decreasing Low-Density Lipoprotein and Improving Gut Microbiota.

BACKGROUND/AIMS: The prevalence of hyperlipidemia is increasing rapidly. The role of Coreopsis tinctoria (CT) in amending lipid metabolism in hyperlipidemia patients has not been reported. This study aims to evaluate the role of CT in altering lipid metabolism in hyperlipidemia patients and to explore the possible mechanisms mediated by gut microbiota in hyperlipidemia mice models. METHODS: A retrospective analysis in 40 hyperlipidemia patients was conducted, in which 20 patients took fenofibrate and another 20 patients normatively drank water with CT. Hyperlipidemia mice models were also established. Blood biochemical tests were performed using an automatic biochemical analyzer. Liver histopathology was observed by hematoxylin and eosin staining. Ileocecal samples were collected from mice, and bacterial DNA was extracted and sequenced by MiSeq sequencing. Bacterial composition and differences were analyzed. RESULTS: In hyperlipidemia patients, CT was associated with decreased triglyceride and low-density lipoprotein (LDL) levels without liver injury. The experimental hyperlipidemia model also verified a similar result. Gut microbial richness and diversity were significantly decreased in hyperlipidemic mice, but increased after CT treatment. Bacterial communities were significantly differentiated between normal controls and hyperlipidemic mice. CT administration improved gut microbiota composition to an approximately normal status. Meanwhile, CT administration attenuated bacterial alterations at the class, order, family, and genus levels in hyperlipidemic mice. Importantly, the genera Barnesiella, Lactobacillus, and Helicobacter achieved high discriminatory power in hyperlipidemic mice relative to normal controls. CONCLUSIONS: CT can modulate blood lipid metabolism with improvement of liver function by decreasing LDL and improving gut microbiota compositions. These findings may provide novel therapeutic strategies for patients with hyperlipidemia.

Synthesis of nanomedicines by nanohybrids conjugating ginsenosides with auto-targeting and enhanced MRI contrast for liver cancer therapy.

A new methodology has been developed with conjugating nanoparticles (NPs) with an active ingredient of Chinese herbs for nanomedicines with auto-targeting and enhanced magnetic resonance imaging (MRI) for liver cancer therapy. Fe@Fe3O4 NPs are first synthesized via the programed microfluidic process, whose surfaces are first modified with -NH2 groups using a silane coupling technique that uses (3-aminopropyl)trimethoxysilane (APTMS) as the coupling reagent and are subsequently activated by the bifunctional amine-active cross-linker [e.g. disuccinimidyl suberate (DSS)]. The model medicines of ginsenosides pre-activated by APTMS are further cross-linked with activated NPs, forming the desired nanomedicines (Nano-Fe-GSS). Sizes and structures of Fe@Fe3O4 NPs were characterized by transmission electron microscopy and X-ray diffraction, revealing that their core-shell structures consist of amorphous boron doped Fe cores and partial crystalline Fe3O4 shells. The accomplishment of coupling reactions in the final nanomedicines is confirmed by the characterization of the composition of NPs and Nano-Fe-GSS via X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FT-IR) spectroscopy. The nanoparticles' effects as MRI contrast agents are further investigated by comparing the T2 weighted spin echo imaging (T2WI) in livers before and after intravenous injection and intragastric administration of nanomedicines. The results indicate that these nanomedicines possess enhanced MRI effects. Investigation of the toxicity and metabolism of Nano-Fe-GSS suggests that they are safe to related vital organs. The results provide an efficient alternative route to synthesize desired multi-functional nanomedicines based on NPs and the active ingredients of Chinese herbs, which can promote their potential synergistic effects in anti-tumor therapy.

Interface interaction induced ultra-dense nanoparticles assemblies.

We demonstrate a simple and clean physical methodology for fabricating such nanoparticle assemblies (dense arrays and/or dendrites) related to the interfacial interaction between the constructed materials and the anodized aluminum oxide (AAO) porous templates. The interfacial interaction can be regulated by the surface tension of the constructed materials and the AAO membrane, and the AAO-template structure, such as pore size, membrane thickness and surface morphologies. Depending on the interfacial interaction between the constructed materials and the AAO templates, NP arrays with mean particle diameters from 3.8 ± 1.0 nm to 12.5 ± 2.9 nm, mean inter-edge spacings from 3.5 ± 1.4 nm to 7.9 ± 3.4 nm and areal densities from 5.6 × 10(11) NPs per cm(2) to 1.5 × 10(12) NPs per cm(2) are fabricated over large areas (currently ~2 cm × 3 cm). The fabrication process includes firstly thermal evaporation of metal layers no more than 10 nm thick on the pre-coated Si wafer by AAO templates with a thickness of less than 150 nm and mean pore sizes no more than 12 nm, and then removal of the AAO templates. The NP arrays can be stable for hours at a temperature slightly below the melting point of the constructed materials (e.g., ~800 °C for Au NPs for 4 hours) with little change in size and inter-particle separation. Using one of them (e.g., 11.8 nm Au NPs) as growth-oriented catalysts, ultra-thin (12.1 ± 2.3 nm) dense nanowires can be conveniently obtained. Furthermore, dendrite superstructures can be generated easily from eutectic alloy NPs with diameters of ~10 nm pre-formed by thermal evaporation of metal layers more than 20 nm thick on surface-patterned thick AAO templates (e.g., 500 nm). The resulting dendrites, dense arrays and other superstructures (i.e., nanorods and nanowires) formed using NP arrays as catalysts, should have broad applications in catalysis, information technology, photovoltaics and biomedical engineering.