Multifunctional composite soluble microneedle patch based on "one stone, three birds" strategy for promoting the healing of infectious wounds.

The colonisation of microorganisms such as bacteria forms a biofilm barrier on the wound's surface, preventing or delaying the penetration of antibacterial drugs. At the same time, continuous bacterial infection can cause oxidative stress and an inflammatory response and hinder angiogenesis, resulting in difficult wound healing. Based on the "one stone, three birds" strategy, a multi-functional nanoparticle composite soluble microneedle was designed and developed to solve this dilemma better. Ginsenoside-liposomes(R-Lipo) were prepared by ginsenoside Rg3, which had the effect of promoting repair, instead of cholesterol, and loaded with berberine (Ber), the antibacterial component of Coptis, together with polydopamine (PDA), which had anti-inflammatory and antioxidant properties, into microneedles based on hyaluronic acid (PDA/R-Lipo@BerMN). PDA/R-Lipo@BerMN tip can penetrate and destroy the integrity of the biofilm, dissolve under the action of hyaluronidase in the skin, and gradually release the drug to achieve rapid antibacterial, anti-inflammatory, antioxidant, and proliferation. As expected, the PDA/R-Lipo@BerMN patch effectively cleared ROS during wound closure, further promoted M2 macrophage polarisation, eradicated bacterial infection, and regulated the immune microenvironment, promoting inflammation suppression, collagen deposition, angiogenesis, and tissue regeneration.

Hybrid nanopotentiators with dual cascade amplification for glioma combined interventional therapy.

Glioma is an aggressive malignant brain tumor with a very poor prognosis for survival. The poor tumor targeting efficiency and tumor microenvironment penetration barrier also as troubles inhibited the effective glioma chemotherapy. Here, we design a core-shell structure cascade amplified hybrid catalytic nanopotentiators CFpAD with DM1 encapsulated to overcome the glioma therapeutic obstacles. NIR laser-based BBB penetrating enhances the tumor accumulation of CFpAD. When CFpAD, as the cascade amplified drug, is treated on the cancer cells, the bomb-like CFpAD releases gold nanoparticles as glucose oxidase (GOx) and ferric oxide nanoparticles (FNPs) as peroxides (POx) after blasting, producing ROS via a cascade amplification for tumor cell apoptosis. Gold nanoparticles can rest CAFs and reduce ECM secretion, achieving deep penetration of CFpAD. Moreover, CFpAD also cuts off the nutritional supply of the tumor, reduces the pH value, and releases free radicals to destroy the cancer. The glioma cell viability was significantly decreased through DNA damage and ROS aggregation due to the DM1-based chemotherapy synergistically combined with interventional photothermal therapy (IPTT) and radiotherapy (RT). This domino cascade amplified loop, combined with starvation therapy with IPTT and RT, has good tumor penetration and outstanding antitumor efficacy, and is a promising glioma treatment system.

Inflammatory macrophage reprogramming strategy of fucoidan microneedles-mediated ROS-responsive polymers for rheumatoid arthritis.

During the pathogenesis of rheumatoid arthritis, inflammatory cells usually infiltrate synovial tissues, notably, M1-type macrophages, whose redox imbalance leads to the degradation of joint structures and deterioration of function. Natural active products play a vital role in immune modulation and antioxidants. In this study, we constructed a ROS-responsive nanoparticle called FTL@SIN, which consists of fucoidan (Fuc) and luteolin (Lut) connected by a ROS-responsive bond, Thioketal (TK), and encapsulated with an anti-rheumatic drug, Sinomenine (SIN), for synergistic anti-inflammatory effects. The FTL@SIN is then dispersed in high molecular weight Fuc-fabricated dissolvable microneedles (FTL@SIN MNs) for local administration. Therapy of FTL@SIN MNs afforded a significant decrease in macrophage inflammation while decreasing key pro-inflammatory cytokines and repolarizing M1 type to M2 type, thereby ameliorating synovial inflammation, and promoting cartilage repair. Additionally, our investigations have revealed that Fucoidan (Fuc) demonstrates synergistic effects, exhibiting superior mechanical strength and enhanced physical stability when compared to microneedles formulated solely with hyaluronic acid. This study combines nanomedicine with traditional Chinese medicine, a novel drug delivery strategy that presents a promising avenue for therapeutic intervention in rheumatoid arthritis.

Marine polysaccharides: Biological activities and applications in drug delivery systems.

The ocean is the common home of a large number of marine organisms, including plants, animals, and microorganisms. Researchers can extract thousands of important bioactive components from the oceans and use them extensively to treat and prevent diseases. In contrast, marine polysaccharide macromolecules such as alginate, carrageenan, Laminarin, fucoidan, chitosan, and hyaluronic acid have excellent physicochemical properties, good biocompatibility, and high bioactivity, which ensures their wide applications and strong therapeutic potentials in drug delivery. Drug delivery systems (DDS) based on marine polysaccharides and modified marine polysaccharide molecules have emerged as an innovative technology for controlling drug distribution on temporal, spatial, and dosage scales. They can detect and respond to external stimuli such as pH, temperature, and electric fields. These properties have led to their wide application in the design of novel drug delivery systems such as hydrogels, polymeric micelles, liposomes, microneedles, microspheres, etc. In addition, marine polysaccharide-based DDS not only have smart response properties but also can combine with the unique biological properties of the marine polysaccharide base to exert synergistic therapeutic effects. The biological activities of marine polysaccharides and the design of marine polysaccharide-based DDS are reviewed. Marine polysaccharide-based responsive DDS are expected to provide new strategies and solutions for disease treatment.

Resveratrol nanocrystals based dissolving microneedles with highly efficient for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common immune disease characterized mainly by erosive arthritis with extensive clinical sequelae. Resveratrol (Res) has pharmacological effects in the treatment of RA, but it has not been widely used in the clinic due to its poor water solubility and low bioavailability. In this study, a drug delivery system (Res-NC MNs) of dissolved microneedles (MNs) loaded with Res nanocrystals (NC) was designed for the treatment of RA. Res-NC MNs can improve the drawbacks of long-term oral drug delivery with toxic side effects and low compliance associated with intra-articular drug delivery. In this study, Res-NC was prepared by media milling and loaded into soluble microneedles prepared from hyaluronic acid (HA) by vacuum casting for the treatment of RA. HA has high mechanical strength and can penetrate the cuticle layer of the skin for effective drug delivery. In in vivo pharmacodynamic experiments, Res-NC MNs achieved better therapeutic efficacy in the treatment of RA compared with oral Res. These findings suggest that Res-NC MNs may be an effective and promising drug delivery strategy for the treatment of RA.

A microthrombus-driven fixed-point cleaved nanosystem for preventing post-thrombolysis recurrence via inhibiting ferroptosis.

Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.

Spatial and temporal evolutionary characteristics of landscape ecological risks and their drivers on the Qinghai-Tibet Plateau.

The changes in landscape ecological risk (LER) of the Qinghai-Tibet Plateau (QTP) profoundly affect the ecological environment of China and the world. We measured the evolution of the LER level and its driving factors through the past 40 years using meteorological data, population density information, and land use data acquired through remote sensing monitoring techniques spanning the years 1980 to 2020. Several key findings were derived: (1) The overall LER of the QTP was at a medium level during 1980-2020, with a fluctuating but decreasing overall trend. (2) Between 1980 and 2020, the spatial distribution of LER in the QTP was high in the west and low in the east; the LER level of the six provinces (districts) showed an overall decrease. (3) During 2000-2020, the LER of the QTP was influenced by a complex mechanism of action. The interactions between different influencing factors were mainly non-linear reinforcement and two-factor reinforcement, and factor interaction significantly enhanced the effect on LER. The findings are of significance for the prevention, control, and management of LER in the QTP.

Plant exosome nanovesicles (PENs): green delivery platforms.

Natural plants have been attracting increasing attention in biomedical research due to their numerous benefits. Plant exosome-derived vesicles, some of the plant's components, are small nanoscale vesicles secreted by plant cells. These vesicles are rich in bioactive substances and play significant roles in intercellular communication, information transfer, and maintaining homeostasis in organisms. They also hold promise for treating diseases, and their vesicular structures make them suitable carriers for drug delivery, with large-scale production feasible. Therefore, this paper aims to provide an overview of nanovesicles from different plant sources and their extraction methods. We also outline the biological activities of nanovesicles, including their anti-inflammatory, anti-viral, and anti-tumor properties, and systematically introduce their applications in drug delivery. These applications include transdermal delivery, targeted drug delivery, gene delivery, and their potential use in the modern food industry. This review provides new ideas and methods for future research on plant exosomes, including their empowerment by artificial intelligence and gene editing, as well as their potential application in the biomedicine, food, and agriculture industries.

Conventional Understanding of SARS-CoV-2 Mpro and Common Strategies for Developing Its Inhibitors.

The Coronavirus Disease 2019 (COVID-19) pandemic has brought a widespread influence on the world, especially in the face of sudden coronavirus infections, and there is still an urgent need for specific small molecule therapies to cope with possible future pandemics. The pathogen responsible for this pandemic is Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and understanding its structure and lifecycle is beneficial for designing specific drugs of treatment for COVID-19. The main protease (Mpro ) which has conservative and specific advantages is essential for viral replication and transcription. It is regarded as one of the most potential targets for anti-SARS-CoV-2 drug development. This review introduces the popular knowledge of SARS-CoV-2 Mpro in drug development and lists a series of design principles and relevant activities of advanced Mpro inhibitors, hoping to provide some new directions and ideas for researchers.

Novel pH-responsive E-selectin targeting natural polysaccharides hybrid micelles for diabetic nephropathy.

Diabetic nephropathy (DN) is an important complication of diabetes and is the main cause of end-stage renal disease. The pathogenesis of DN is complex, including glucose and lipid metabolism disorder, inflammation, and so on. Novel hybrid micelles loaded Puerarin (Pue) based on Angelica sinensis polysaccharides (ASP) and Astragalus polysaccharide (APS) were fabricated with pH-responsive ASP-hydrazone-ibuprofen (BF) materials (ASP-HZ-BF, SHB) and sialic acid (SA) modified APS-hydrazone-ibuprofen materials (SA/APS-HZ-BF, SPHB) by thin-film dispersion method. The SA in hybrid micelles can specifically bind to the E-selectin receptor which is highly expressed in inflammatory vascular endothelial cells. The loaded Pue could be accurately delivered to the inflammatory site of the kidney in response to the low pH microenvironment. Overall, this study provides a promising strategy for developing hybrid micelles based on natural polysaccharides for the treatment of diabetic nephropathy by inhibiting renal inflammatory reactions, and antioxidant stress.

Novel dual CAFs and tumour cell targeting pH and ROS dual sensitive micelles for targeting delivery of paclitaxel to liver cancer.

Tumour development is not only an independent event of genetic mutation and overgrowth of tumour cells but is the result of a synergistic interaction between a malignant tumour and its surrounding tumour stromal microenvironment. In this paper, we address the shortcomings of current tumour therapy by focussing on the tumour itself and the surrounding microenvironment to achieve a two-pronged targeting model. In this paper, a dual-targeting, pH/reactive oxygen species (ROS) sensitive nano-drug delivery system for tumour cells and CAFs was designed. A hyaluronic acid (HA) with CD44 receptor targeting on the surface of tumour cells was selected as the main carrier material, and a dipeptide Z-glycine-proline (ZGP) with specific targeting of fibroblast activating protein (FAP) on the surface of CAFs was modified on HA to achieve precise targeting of CAFs, open the physical barrier of tumour cells and improve the deep penetration effect of the tumour, while introducing thioketone bond and ketone condensation bond to take advantage of the highly reactive ROS and low pH microenvironment at the tumour site to achieve chemical bond breaking of nano micelles encapsulating paclitaxel (PTX), drug release, and thus drug aggregation at the tumour site and improved bioavailability of the drug.

Anti-inflammatory Activity of Gegen Decoction and Its Modulatory Mechanism on the NF-κB and MAPK Signaling Pathways.

Gegen Decoction as anti-inflammatory medicine is used in clinic widespread, however the specific anti-inflammatory molecular mechanism of Gegen Decoction is still unclear. The purpose was to study the anti-inflammatory activity of Gegen Decoction in vivo and to research its anti-inflammatory molecular mechanism. The content of main essential components in Gegen Decoction were determined by HPLC method. The anti-inflammatory activity of Gegen Decoction was confirmed through in vivo animal experiments. Furthermore, RAW 264.7 cells were stimulated by lipopolysaccharides to induce inflammatory reaction, the modulatory effect of Gegen Decoction on the activation process of mitogen-activated protein kinases and nuclear factor-κB signaling pathways was investigated. The content of puerarin was the highest among all the index components. Gegen Decoction inhibited carrageenan-induced paw edema in rats and xylene-induced ear swelling in mice. Gegen Decoction had no obvious toxicity against RAW 264.7 cells at the concentrations of 10-40 mg/mL; significantly inhibited the release of nitric oxide, prostaglandin E2, tumor necrosis factor-α and interleukin-6; down-regulated the high expression of inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2. It inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs)/extracellular regulated protein kinases (ERK)/c-Jun N-terminal kinase (JNK), the degradation of nuclear factor-κB (NF-κB)/inhibitor of NF-κB-α (IκB-α) and the nuclear translocation of NF-κB/p65 into nucleus. Gegen Decoction exerts significant anti-inflammatory activity, mainly by blocking the activation of both MAPKs and NF-κB pathway.

3D Printing Technology Based on Versatile Gelatin-Carrageenan Gel System for Drug Formulations.

Currently, there is a shortage of pediatric medicines on the market, and 3D printing technology can more flexibly produce personalized medicines to meet individual needs. The study developed a child-friendly composite gel ink (carrageenan-gelatin), created 3D models by computer-aided design technology, then produced personalized medicines using 3D printing to improve the safety and accuracy of medication for pediatric patients. An in-depth understanding of the printability of different formulations was obtained by analyzing the rheological and textural properties of different gel inks and observing the microstructure of different gel inks, which guided the formulation optimization. Through formulation optimization, the printability and thermal stability of gel ink were improved, and F6 formulation (carrageenan: 0.65%; gelatin: 12%) was selected as the 3D printing inks. Additionally, a personalized dose linear model was established with the F6 formulation for the production of 3D printed personalized tablets. Moreover, the dissolution tests showed that the 3D printed tablets were able to dissolve more than 85% within 30 min and had similar dissolution profiles to the commercially available tablets. This study demonstrates that 3D printing is an effective manufacturing technique that allows for flexible, rapid, and automated production of personalized formulations.

α-Lipoic acid loaded hollow gold nanoparticles designed for osteoporosis treatment: preparation, characterization and in vitro evaluation.

Osteoporosis is a common disease among the ageing society. Oxidative stress caused by excessive accumulation of reactive oxygen species (ROS) is the aetiology of osteoporosis. α-Lipoic acid (ALA) is an antioxidant in the body, which can eliminate excess ROS in the body and inhibits levels of oxidative stress in cells. Herein, we designed PEGylated hollow gold nanoparticles (HGNPs) loaded with ALA (mPEG@HGNPs-ALA) to remove ROS in the treatment of osteoporosis. First, mPEG@HGNPs with a particle size of ∼63 nm has been successfully synthesized. By comparing the drug loading of mPEG@HGNPs, it was concluded that the optimal mass ratio of mPEG@HGNPs (calculated by the amount of gold) to ALA was ∼1:2. ABTS antioxidant assay showed that free radical removal ability. In vitro results revealed that the preparation had good biocompatibility. At the gold concentration of 1-150 µg/mL, the cell viability of mPEG@HGNPs was more than 100%, which indicated that it could promote the proliferation of osteoblasts. What's more, mPEG@HGNPs-ALA could effectively remove the ROS caused by H2O2 injury and improve the cell viability. According to these results, it can be considered that mPEG@HGNPs-ALA has the potential to treat osteoporosis.