Flexible nano-liposomes-encapsulated recombinant UL8-siRNA (r/si-UL8) based on bioengineering strategy inhibits herpes simplex virus-1 infection.

Herpes simplex virus-1 (HSV-1) infection can cause various diseases and the current therapeutics have limited efficacy. Small interfering RNA (siRNA) therapeutics are a promising approach against infectious diseases by targeting the viral mRNAs directly. Recently, we employed a novel tRNA scaffold to produce recombinant siRNA agents with few natural posttranscriptional modifications. In this study, we aimed to develop a specific prodrug against HSV-1 infection based on siRNA therapeutics by bioengineering technology. We screened and found that UL8 of the HSV-1 genome was an ideal antiviral target based on RNAi. Next, we used a novel bio-engineering approach to manufacture recombinant UL8-siRNA (r/si-UL8) in Escherichia coli with high purity and activity. The r/si-UL8 was selectively processed to mature si-UL8 and significantly reduced the number of infectious virions in human cells. r/si-UL8 delivered by flexible nano-liposomes significantly decreased the viral load in the skin and improved the survival rate in the preventive mouse zosteriform model. Furthermore, r/si-UL8 also effectively inhibited HSV-1 infection in a 3D human epidermal skin model. Taken together, our results highlight that the novel siRNA bioengineering technology is a unique addition to the conventional approach for siRNA therapeutics and r/si-UL8 may be a promising prodrug for curing HSV-1 infection.

A novel recombinant ORF7-siRNA delivered by flexible nano-liposomes inhibits varicella zoster virus infection.

BACKGROUND: Varicella zoster virus (VZV), which is a human restricted alpha-herpesvirus, causes varicella (chickenpox) and zoster (shingles). The subsequent post-herpetic neuralgia (PHN) due to VZV infection is excruciating for most patients. Thus, developing specific therapeutics against VZV infection is imperative. RNA interference (RNAi) represents an effective approach for alternative antiviral therapy. This study aimed to develop a novel anti-VZV therapeutics based on RNAi. RESULTS: In this study, we screened and found the open reading frame 7 (ORF7) of the VZV genome was an ideal antiviral target based on RNAi. Therefore, a novel siRNA targeting ORF7 (si-ORF7) was designed to explore the potential of RNAi antiviral treatment strategy toward VZV. We used a bio-engineering approach to manufacture recombinant siRNA agents with high yield in E. coli. Then, the efficacy of recombinant ORF7-siRNA (r/si-ORF7) in inhibiting VZV infection both in cellular level and 3D human epidermal skin model was evaluated. The r/si-ORF7 was proved to inhibit the VZV replication and reduce the virus copy numbers significantly in vitro. Furthermore, flexible nano-liposomes were established to deliver r/si-ORF7 to 3D human epidermal skin model and found r/si-ORF7 also could inhibit the VZV infection, thus maintaining normal skin morphology. CONCLUSIONS: Taken together, our results highlighted that transdermal administration of antiviral r/si-ORF7 was a promising therapeutic strategy for functional cure of VZV infection.

Chemiluminescent carbon nanodots for dynamic and guided antibacteria.

Advanced antibacterial technologies are needed to counter the rapid emergence of drug-resistant bacteria. Image-guided therapy is one of the most promising strategies for efficiently and accurately curing bacterial infections. Herein, a chemiluminescence (CL)-dynamic/guided antibacteria (CDGA) with multiple reactive oxygen species (ROS) generation capacity and chemiexcited near-infrared emission has been designed for the precise theranostics of bacterial infection by employing near-infrared emissive carbon nanodots (CDs) and peroxalate as CL fuels. Mechanistically, hydrogen peroxide generated in the bacterial microenvironment can trigger the chemically initiated electron exchange between CDs and energy-riched intermediate originated from the oxidized peroxalate, enabling bacterial induced inflammation imaging. Meanwhile, type I/II photochemical ROS production and type III ultrafast charge transfer from CDs under the self-illumination can inhibit the bacteria proliferation efficiently. The potential clinical utility of CDGA is further demonstrated in bacteria infected mice trauma model. The self-illuminating CDGA exhibits an excellent in vivo imaging quality in early detecting wound infections and internal inflammation caused by bacteria, and further are proven as efficient broad-spectrum antibacterial nanomedicines without drug-resistance, whose sterilizing rate is up to 99.99%.

Macrophage-Targeted Dextran Sulfate-Dexamethasone Conjugate Micelles for Effective Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic immune disease that causes joint affection and even disability. Activated macrophages play an important role in the pathogenesis and progression of RA by producing pro-inflammatory factors. The use of dexamethasone (DXM) is effective in relieving the intractable pain and inflammatory progression of RA. However, long-term use of DXM is strongly associated with increased rates of diabetes, osteoporosis, bone fractures, and mortality, which hinders its clinical use. In this study, the dextran sulfate-cisaconitic anhydride-dexamethasone (DXM@DS-cad-DXM) micelles were prepared to treat RA by selectively recognizing scavenger receptor (SR) on the activated macrophages. The potent targeting property of DXM@DS-cad-DXM micelles to SR was by fluorescence microscope. Additionally, the effective accumulation and powerful anti-inflammatory activity of DXM@DS-cad-DXM micelles were observed in the inflamed joints of adjuvant-induced arthritis (AIA) rats after intravenous administration. Overall, DXM@DS-cad-DXM micelles are a potentially effective nanomedicine for targeted therapy of RA.

In Situ Confining Citric Acid-Derived Carbon Dots for Full-Color Room-Temperature Phosphorescence.

Room-temperature phosphorescence has received much attention owing to its potential applications in information encryption and bioelectronics. However, the preparation of full-color single-component-derived phosphorescent materials remains a challenge. Herein, a facile in situ confining strategy is proposed to achieve full-color phosphorescent carbon dots (CDs) through rapid microwave-assisted carbonization of citric acid in NaOH. By tuning the mass ratio of citric acid and NaOH, the obtained CDs exhibit tunable phosphorescence wavelengths ranging from 483 to 635 nm and alterable lifetimes from 58 to 389 ms with a synthesis yield of up to 83.7% (>30 g per synthesis). Theoretical calculations and experimental results confirm that the formation of high-density ionic bonds between cations and CDs leads to efficient afterglow emission via the dissociation of CD arrangement, and the evolution of the aggregation state of CDs results in redshifted phosphorescence. These findings provide a strategy for the synthesis of new insights into achieving and manipulating room-temperature phosphorescent CDs, and prospect their applications in labeling and information encryption.

Co-Polymer Carrier with Dual Advantages of Cartilage-Penetrating and Targeting Improves Delivery and Efficacy of MicroRNA Treatment of Osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disease affecting nearly 400 million people with no efficient etiological therapies. OA is primarily identified by cartilage destruction, and gradual degeneration of the whole joint would happen when the OA progresses. Hence, cartilage has been identified as the primary therapeutic target of OA. Unfortunately, numerous barriers block the delivery of therapeutic agents into cartilage, including avascular traits and high hardness of the extracellular matrix. Herein, a cartilage-targeting peptide (CAP) modified polyvinylamine (PVAm)- poly (lactic-co-glycolic acid) (PLGA) copolymer (CAP-PVAm-PLGA) is designed, which can form spherical nanoparticles with the r-miR-140 (CPP-NPs). CPP-NPs possessed enhanced mechanical properties due to the introduction of PLGA to vehicles. Meanwhile, CAP endowed the cartilage targeting which facilitated CPP-NPs localization in cartilage. With such dual advantages, CPP-NPs exhibited outstanding penetrability and accumulation in cartilage even subchondral bone, and can penetrate to a depth of 1000 µm into human cartilage. The degeneration area of cartilage is reduced by 65% and synovial inflammation score by 80% in OA mice, and the microarchitecture of subchondral bone is also ameliorated. These studies established a promising platform for therapeutic RNA delivery in OA therapy that overcame the cartilage barriers.

Flexible nano-liposomes-based transdermal hydrogel for targeted delivery of dexamethasone for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that can lead to synovitis, cartilage destruction, and even joint damage. Dexamethasone (DEX) is a commonly used agent for RA therapy on inflammation manage. However, the traditional administering DEX is hampered by low efficiency and obvious adverse effects. Therefore, in order to efficiently deliver DEX to RA inflamed joints and overcome existing deficiencies, we developed transdermal formation dextran sulfate (DS) modified DEX-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel), validated their transdermal efficiency, evaluated its ability to target activated macrophages, and its anti-inflammatory effect. The DS-FLs/DEX exhibited excellent biocompatibility, sustainable drug release, and high uptake by lipopolysaccharide (LPS)-activated macrophages. Furthermore, the DS-FLs/DEX hydrogel showed desired skin permeation as compared with regular liposome hydrogel (DS-RLs/DEX hydrogel) due to its good deformability. In vivo, when used the AIA rats as RA model, the DS-FLs/DEX hydrogel can effectively penetrate and accumulate in inflamed joints, significantly improve joint swelling in RA rats, and reduce the destructive effect of RA on bone. Importantly, the expression of inflammatory cytokines in joints was inhibited and the system toxicity did not activate under DS-FLs/DEX hydrogel treatment. Overall, these data revealed that the dextran sulfate (DS) modified DEX-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel) can prove to be an excellent drug delivery vehicle against RA.

Meter-scale chemiluminescent carbon nanodot films for temperature imaging.

Chemiluminescence (CL), as one class of luminescence driven by chemical reaction, exhibits obvious temperature-dependence in its light emission process. Herein, temperature-dependent CL emission of carbon nanodots (CDs) in the chemical reaction of peroxalate and hydrogen peroxide is demonstrated and temperature imaging based on the temperature-dependent CL has been established for the first time. In detail, the temperature-dependent CL emission of CDs in the chemical reaction of peroxalate and hydrogen peroxide is observed, and the linear relationship between the CL intensity and temperature is demonstrated in both the CL solution and film, enabling their applications in temperature sensing and imaging capabilities. The increase of the CL emission with temperature can be attributed to the accelerated electron exchange between the CDs and intermediate generated in the peroxalate system. Meter-scale chemiluminescent CD films have been constructed. The CL sensor based on the films presents a high spatial resolution of 0.4 mm and an outstanding sensitivity of 0.08 °C-1, which is amongst the best values for the thermographic luminophores. With the unique temperature response and flexible properties, non-planar, meter-scale and sensitive palm temperature imaging has been achieved. These findings present new opportunities for designing CL-based temperature probes and thermography.

Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer.

Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.