A erythrocyte-platelet hybrid membrane coated biomimetic nanosystem based on ginsenosides and PFH combined with ultrasound for targeted delivery in thrombus therapy.

Thrombus is one of the culprits for global health problems. However, most current antithrombotic drugs are limited by restricted targeting ability and a high risk of systemic bleeding. A hybrid cell membrane-coated biomimetic nanosystem (PM/RM@PLGA@P/R) was constructed in this paper to fulfil the targeted delivery of ginsenoside (Rg1) and perfluorohexane (PFH). Poly lactic-co-glycolic acid (PLGA) is used as carriers to coat Rg1 and PFH. Thanks to the camouflage of erythrocyte membrane (RM) and platelet membrane (PM), the nanosystem in question possesses remarkable features including immune escape and self-targeting. Therefore, a compact nano-core with PLGA@P/R was formed, with a hybrid membrane covering the surface of the core, forming a "core-shell" structure. With its "core-shell" structure, this nanoparticle fancifully combines the advantages of both PFH (the low-intensity focused ultrasound (LIFU)-responsive phase-change thrombolysis) and Rg1(the antioxidant, anti-inflammatory and anticoagulant abilities). Meanwhile, PM/RM@PLGA@P/R nanoparticles exhibits superior in-vitro performance in terms of ROS scavenging, anticoagulant activity and immune escape compared with those without cell membranes (PLGA@P/R). Furthermore, in the animal experiment in which the tail vein thrombosis model was established by injecting k-carrageenan, the combined treatment of LIFU and PM/RM@PLGA@P/R showed a satisfactory antithrombotic efficiency (88.20 %) and a relatively higher biological safety level. This strategy provides new insights into the development of more effective and safer targeted biomimetic nanomedicines for antithrombotic treatments, possessing potential application in synergistic therapy field.

Rational design of a minimum nanoplatform for maximizing therapeutic potency: Three birds with one stone.

Therapeutic modalities and drug formulations play a crucial and prominent role in actualizing effective treatment and radical cures of tumors. However, the therapeutic efficiency was severely limited by tumor recurrence and complex multi-step preparation of formulation. Therefore, the exploration of novel nanoparticles via a simple and green synthesis process for conquering traditional obstacles and improving therapeutic efficiency is an appealing, yet remarkably challenging task. Herein, a universal nanoplatform allows all cancerous cell-targeting, acid-responsive, cell imaging, synergistic chemotherapy, and nucleolar targeted phototherapy function was tactfully designed and constructed by using chemotherapeutic agents ursolic acid (UA), sorafenib (SF), and carbon dots (CDs) photosensitizers (PSs). The designed US NPs were formed by self-assembly of UA and SF associated with electrostatic, π-π stacking, and hydrophobic interactions. After hydrogen bonding reaction with CDs, the obtained (denoted as USC NPs) have a relatively uniform size of an average 125.6 nm, which facilitated the favorable accumulation of drugs at the tumor region through a potential enhanced permeability and retention (EPR) effect as compared to their counterpart of free CDs solution. Both in vitro and in vivo studies revealed that the advanced platform commenced synergistic anticancer therapeutic potency, imperceptible systematical toxicity, and remarkable reticence towards drug-resistant cancer cells. Moreover, the CDs PSs possess intrinsic nucleolus-targeting ability. Taken together, this theranostics system can fully play the role of "killing three birds with one stone" in a safe manner, implying a promising direction for exploring treatment strategies for cancer and endowing them with great potential for future translational research and providing a new vision for the advancing of an exceptionally forceful protocol for practical cancer therapy.

Current Advances and Prospects in Carbon Nanomaterials-based Drug Deliver Systems for Cancer Therapy.

The in-depth intersection between nanoscience and oncology comes from the fact that nanomaterials are in a similar dimension to basic biomolecules. Drug delivery systems (DDSs), which are either targeted to a particular site or intended for the controlled release in a particular position, have been studied extensively at the nanoscale and are, by far, the most advanced technology in the area of nanoparticle applications. This, consequently lead to the improvement and development of convenient administration routes, lower toxicity, fewer side effects, and extended drug life cycle. Carbon nanomaterials (CNMs) with favorable size and unique fluorescence properties, which was considered an ideal candidate to transport or deliver therapeutic drugs to specific targets in a controlled manner. The development of DDSs based on them constitutes an interesting topic in highly effective and universal therapies to achieve better therapeutic outcomes and reduce the side effects of malignancies. In this review, the cutting-edge progress of CNMs in DDSs was comprehensively summarized. Additionally, the emphasis was placed on the applications of CNMs including fullerene, graphene, carbon nanotubes (CNTs), carbon dots (CDs), and nano-diamonds (NDs) in drug delivering. Further, we gave some insights into the future direction and foreseeable challenges of DDSs based on CNMs used in cancer therapy, which we hope these inspirations in DDSs associated with anti-cancer therapy will provide perspectives in designing new drugs for further tumor treatment.

Biomedical engineered nanomaterials to alleviate tumor hypoxia for enhanced photodynamic therapy.

Photodynamic therapy (PDT), as a highly selective, widely applicable, and non-invasive therapeutic modality that is an alternative to radiotherapy and chemotherapy, is extensively applied to cancer therapy. Practically, the efficiency of PDT is severely hindered by the existence of hypoxia in tumor tissue. Hypoxia is a typical hallmark of malignant solid tumors, which remains an essential impediment to many current treatments, thereby leading to poor clinical prognosis after therapy. To address this issue, studies have been focused on modulating tumor hypoxia to augment the therapeutic efficacy. Although nanomaterials to relieve tumor hypoxia for enhanced PDT have been demonstrated in many research articles, a systematical summary of the role of nanomaterials in alleviating tumor hypoxia is scarce. In this review, we introduced the mechanism of PDT, and the involved therapeutic modality of PDT for ablation of tumor cells was specifically summarized. Moreover, current advances in nanomaterials-mediated tumor oxygenation via oxygen-carrying or oxygen-generation tactics to alleviate tumor hypoxia are emphasized. Based on these considerable summaries and analyses, we proposed some feasible perspectives on nanoparticle-based tumor oxygenation to ameliorate the therapeutic outcomes, which may provide some detailed information in designing new oxygenation nanomaterials in this burgeneous field.

Protective Effects and Therapeutics of Ginsenosides for Improving Endothelial Dysfunction: From Therapeutic Potentials, Pharmaceutical Developments to Clinical Trials.

The endothelium covers the internal lumen of the entire circulatory system and plays an important modulatory role in vascular homeostasis. Endothelium dysfunction, characterized by a vasoconstrictive, pro-inflammatory, and pro-coagulant state, usually manifests as a significant pathological process of vascular diseases, including hypertension, atherosclerosis (AS), stroke, diabetes mellitus, coronary artery disease, and cancer. Therefore, there is an urgent necessity to seek promising therapeutic drugs or remedies to ameliorate endothelial dysfunction-induced vascular ailments and complications. Recently, much attention has been attached to ginsenosides, the most significant active components of ginseng, which have always been referred to as "all-healing" and widely used for its extensively medicinal value. Surprisingly, ginsenosides have diverse biological activity which might be related to inflammation, apoptosis, oxidative stress, and angiogenesis. In this review, a brief introduction about endothelial dysfunction and ginsenosides was demonstrated, and the emphasis was put on summarizing multi-faceted pharmacological effects and underlying molecular mechanisms of ginsenosides on the endothelium, including vasorelaxation, anti-oxidation, anti-inflammation, and angio-modulation. Beyond that, nanotechnology to improve efficacy and the existing clinical trials of ginsenosides were concluded. Hopefully, our work will give suggestions for promoting clinical application of traditional Chinese medicine, e.g., hypertension, AS, diabetes, ischemic stroke, and cancer. This review provides a comprehensive base of knowledge for ginsenosides to prevention and treatment of vascular injury- related diseases with clinical significance.

A smart dual-drug nanosystem based on co-assembly of plant and food-derived natural products for synergistic HCC immunotherapy.

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.

Cell adhesion molecule-mediated therapeutic strategies in atherosclerosis: From a biological basis and molecular mechanism to drug delivery nanosystems.

Atherosclerosis (AS), characterized by pathological constriction of blood vessels due to chronic low-grade inflammation and lipid deposition, is a leading cause of human morbidity and mortality worldwide. Cell adhesion molecules (CAMs) have the ability to regulate the inflammatory response and endothelial function, as well as potentially driving plaque rupture, which all contribute to the progression of AS. Moreover, recent advances in the development of clinical agents in the cardiovascular field are based on CAMs, which show promising results in the fight against AS. Here, we review the current literature on mechanisms by which CAMs regulate atherosclerotic progression from the earliest induction of inflammation to plaques formation. In particular, we focused on therapeutic strategies based on CAMs inhibitors that prevent leukocyte from migrating to endothelium, including high-affinity antibodies and antagonists, nonspecific traditional medicinal formulas and lipid lowering drugs. The CAMs-based drug delivery nanosystem and the available data on the more reasonable and effective clinical application of CAMs inhibitors have been emphasized, raising hope for further progress in the field of AS therapy.

Co-delivery of Sorafenib and CRISPR/Cas9 Based on Targeted Core-Shell Hollow Mesoporous Organosilica Nanoparticles for Synergistic HCC Therapy.

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.

The effects of ginsenosides on platelet aggregation and vascular intima in the treatment of cardiovascular diseases: From molecular mechanisms to clinical applications.

Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng, has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research.

Redox Recycling-Triggered Peroxidase-Like Activity Enhancement of Bare Gold Nanoparticles for Ultrasensitive Colorimetric Detection of Rare-Earth Ce3+ Ion.

Although it has been demonstrated that rare-earth elements (REEs) disturb and alter the catalytic activity of numerous natural enzymes, their effects on nanomaterial-based 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 Ce3+-activated peroxidase mimetic activity of GNPs is obtained. The introduced Ce3+ can be bound to the bare GNP surface rapidly through electrostatic attraction, after which it donates its electron to the bare GNP. As H2O2 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 Ce3+ is proved to be more efficient in comparison to those of the other reported metal ion activators (e.g., Bi3+, Hg2+, and Pb2+). In addition, it is determined that Ce3+ should directly contact with the gold core to trigger its activation effect. When the surface states of the bare GNPs are altered, the Ce3+-stimulated effect is strongly inhibited. Furthermore, a novel colorimetric method for Ce3+ 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 Ce3+ 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.