Targeting Senescent Cells in Atherosclerosis: Pathways to Novel Therapies.

Targeting senescent cells has recently emerged as a promising strategy for treating age-related diseases, such as atherosclerosis, which significantly contributes to global cardiovascular morbidity and mortality. This review elucidates the role of senescent cells in the development of atherosclerosis, including persistently damaging DNA, inducing oxidative stress and secreting pro-inflammatory factors known as the senescence-associated secretory phenotype. Therapeutic approaches targeting senescent cells to mitigate atherosclerosis are summarized in this review, which include the development of senotherapeutics and immunotherapies. These therapies are designed to either remove these cells or suppress their deleterious effects. These emerging therapies hold potential to decelerate or even alleviate the progression of AS, paving the way for new avenues in cardiovascular research and treatment.

A bioinspired supramolecular nanoprodrug for precision therapy of B-cell non-Hodgkin's lymphoma.

Fludarabine (FA) is still considered as a first-line chemotherapy drug for hematological tumors related to B lymphocytes. However, it is worth noting that the non-specific distribution and non-different cytotoxicity of FA may lead to irreversible consequences such as central nervous system damage such as blindness, coma, and even death. Therefore, it is very important to develop a system to targeting delivery FA. In preliminary studies, it was found that B lymphoma cells would specific highly expressing the sialic acid-binding immunoglobulin-like lectin 2 (known as CD22). Inspired by the specific recognition of sialic acid residues and CD22, we have developed a supramolecular prodrug based on polysialic acid, an endogenous biomacromolecule, achieving targeted-therapy of B-cell non-Hodgkin's lymphoma (B-NHL). Specifically, the prepared hydrophobic reactive oxygen species-responsive FA dimeric prodrug (F2A) interacts with the TPSA, which polysialic acid were modified by the thymidine derivatives, through non-covalent intermolecular interactions similar to "Watson-Crick" base pairing, resulting in the formation of nanoscale supramolecular prodrug (F@TPSA). Cell experiments have confirmed that F@TPSA can be endocytosed by CD22+ B lymphoma cells including Raji and Ramos cells, and there is a significant difference of endocytosis in other leukocytes. Furthermore, in B-NHL mouse model, compared with FA, F@TPSA is determined to have a stronger tumor targeting and inhibitory effect. More importantly, the distribution of F@TPSA in vivo tends to be enriched in lymphoma tissue rather than nonspecific, thus reducing the leukopenia of FA. The targeted delivery system based on PSA provides a new prodrug modification strategy for targeted treatment of B-NHL.

Macrocycle-Based Supramolecular Drug Delivery Systems: A Concise Review.

Efficient delivery of therapeutic agents to the lesion site or specific cells is an important way to achieve "toxicity reduction and efficacy enhancement". Macrocycles have always provided many novel ideas for drug or gene loading and delivery processes. Specifically, macrocycles represented by crown ethers, cyclodextrins, cucurbit[n]urils, calix[n]arenes, and pillar[n]arenes have unique properties, which are different cavity structures, good biocompatibility, and good stability. Benefited from these diverse properties, a variety of supramolecular drug delivery systems can be designed and constructed to effectively improve the physical and chemical properties of guest molecules as needed. This review provides an outlook on the current application status and main limitations of macrocycles in supramolecular drug delivery systems.

Temperature-dependent action of pepper mildew resistance locus O 1 in inducing pathogen immunity and thermotolerance.

Plant diseases tend to be more serious under conditions of high-temperature/high-humidity (HTHH) than under moderate conditions, and hence disease resistance under HTHH is an important determinant for plant survival. However, how plants cope with diseases under HTHH remains poorly understood. In this study, we used the pathosystem consisting of pepper (Capsicum annuum) and Ralstonia solanacearum (bacterial wilt) as a model to examine the functions of the protein mildew resistance locus O 1 (CaMLO1) and U-box domain-containing protein 21 (CaPUB21) under conditions of 80% humidity and either 28 °C or 37 °C. Expression profiling, loss- and gain-of-function assays involving virus-induced gene-silencing and overexpression in pepper plants, and protein-protein interaction assays were conducted, and the results showed that CaMLO1 acted negatively in pepper immunity against R. solanacearum at 28 °C but positively at 37 °C. In contrast, CaPUB21 acted positively in immunity at 28 °C but negatively at 37 °C. Importantly, CaPUB21 interacted with CaMLO1 under all of the tested conditions, but only the interaction in response to R. solanacearum at 37 °C or to exposure to 37 °C alone led to CaMLO1 degradation, thereby turning off defence responses against R. solanacearum at 37 °C and under high-temperature stress to conserve resources. Thus, we show that CaMLO1 and CaPUB21 interact with each other and function distinctly in pepper immunity against R. solanacearum in an environment-dependent manner.

Sialylation: An alternative to designing long-acting and targeted drug delivery system.

Long-acting and specific targeting are two important properties of excellent drug delivery systems. Currently, the long-acting strategies based on polyethylene glycol (PEG) are controversial, and PEGylation is incapable of simultaneously possessing targeting ability. Thus, it is crucial to identify and develop approaches to produce long-acting and targeted drug delivery systems. Sialic acid (SA) is an endogenous, negatively charged, nine-carbon monosaccharide. SA not only mediates immune escape in the body but also binds to numerous disease related targets. This suggests a potential strategy, namely "sialylation," for preparing long-acting and targeted drug delivery systems. This review focuses on the application status of SA-based long-acting and targeted agents as a reference for subsequent research.

Research Progress of Neutrophil-Mediated Drug Delivery Strategies for Inflammation-Related Disease.

As the most abundant white blood cells in humans, neutrophils play a key role in acute and chronic inflammation, suggesting that these cells are a key component of targeted therapies for various inflammation-related diseases. Specific enzyme-responsive or specific ligand-modified polymer nanoparticles are beneficial for improving drug efficacy, reducing toxicity, and enhancing focal site retention. However, there remain significant challenges in biomedical applications of these synthetic polymer nanoparticles, mainly due to their rapid clearance by the reticuloendothelial system. In recent years, biomimetic drug delivery systems such as neutrophils acting directly as drug carriers or neutrophil-membrane-coated nanoparticles have received increasing attention due to the natural advantages of neutrophils. Thus, neutrophil-targeted, neutrophil-assisted, or neutrophil-coated nanoparticles exhibit a prolonged blood circulation time and improved accumulation at the site of inflammation. Despite recent advancements, further clinical research must be performed to evaluate neutrophil-based delivery systems for future biomedical application in the diagnosis and treatment of related inflammatory diseases. In this review, we have summarized new exciting developments and challenges in neutrophil-mediated drug delivery strategies for treating inflammation-related diseases.

Research Progress of the Ion Activity Coefficient of Polyelectrolytes: A Review.

Polyelectrolyte has wide applications in biomedicine, agriculture and soft robotics. However, it is among one of the least understood physical systems because of the complex interplay of electrostatics and polymer nature. In this review, a comprehensive description is presented on experimental and theoretical studies of the activity coefficient, one of the most important thermodynamic properties of polyelectrolyte. Experimental methods to measure the activity coefficient were introduced, including direct potentiometric measurement and indirect methods such as isopiestic measurement and solubility measurement. Next, progress on the various theoretical approaches was presented, ranging from analytical, empirical and simulation methods. Finally, challenges for future development are proposed on this field.

Pathologically triggered in situ aggregation of nanoparticles for inflammation-targeting amplification and therapeutic potentiation.

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

A brief review of polysialic acid-based drug delivery systems.

Polysialic acid (PSA) is a straight-chain homoglycan linked by N-acetylneuraminic acid monomers via α-2, 8- or α-2, 9-glycosidic bonds. As a negatively charged non-glycosaminoglycan, PSA has the remarkable characteristics of non-immunogenicity and biodegradation. Although different in class, PSA is similar to poly(ethylene glycol), and was originally used to increase the stability of the delivery system in circulation to prolong the half-life. As research continues, PSA's application potential in the pharmaceutical field becomes increasingly prominent. It can be used as a biomaterial for protein polysialylation and tissue engineering, and it can be used alone or with other materials to develop multifunctional drug delivery systems. In this article, the results of the bioproduction and biofunction of PSA are introduced, the common strategies for chemical modification of PSA are summarized, and the application progress of PSA-based drug delivery systems is reviewed.

A Mini-Review of Diagnostic and Therapeutic Nano-Tools for Pancreatitis.

Pancreatitis is an inflammatory reaction of pancreatic tissue digestion, edema, bleeding and even necrosis caused by activation of pancreatin due to various causes. In particular, patients with severe acute pancreatitis (SAP) often suffer from secondary infection, peritonitis and shock, and have a high mortality rate. Chronic pancreatitis (CP) can cause permanent damage to the pancreas. Due to the innate characteristics, structure and location of the pancreas, there is no effective treatment, only relief of symptoms. Especially, AP is an unpredictable and potentially fatal disease, and the timely diagnosis and treatment remains a major challenge. With the rapid development of nanomedicine technology, many potential tools can be used to address this problem. In this review, we have introduced the pathophysiological processes of pancreatitis to understanding its etiology and severity. Most importantly, the current progress in the diagnosis and treatment tools of pancreatitis based on nanomedicine is summarized and prospected.

Targeted delivery strategy: A beneficial partner for emerging senotherapy.

Numerous cutting-edge studies have confirmed that the slow accumulation of cell cycle arrested and secretory cells, called senescent cells (SCs), in tissues is an important negative factor, or even the culprit, in age- associated diseases such as non-alcoholic fatty liver, Alzheimer's disease, type 2 diabetes, atherosclerosis, and malignant tumors. With further understanding of cellular senescence, SCs are important effective targets for the treatment of senescence-related diseases, called the Senotherapy. However, existing therapies, including Senolytics (which lyse SCs) and Senostatic (which regulate senescence-associated secretory phenotype), do not have the properties to target SCs, and side effects due to non-specific distribution are one of the hindrances to clinical use of Senotherapy. In the past few decades, targeted delivery has attracted much attention and been developed as a recognized diagnostic and therapeutic novel tool, due to the advantages of visualization of targets, more accurate drug/gene delivery, and ultimately "reduced toxicity and enhanced efficacy". Despite considerable advances in achieving targeted delivery, it has not yet been widely used in Senotherapy. In this review, we clarify the challenge for Senotherapy, then discuss how different targeted strategies contribute to imaging or therapy for SCs in terms of different biomarkers of SCs. Finally, the emerging nano-Senotherapy is prospected.

Polysialylated nanoinducer for precisely enhancing apoptosis and anti-tumor immune response in B-cell lymphoma.

B-cell lymphoma is one of the most common types of lymphoma, and chemotherapy is still the current first-line treatment. However, due to the systemic side effects caused by chemotherapy drugs, traditional regimens have limitations and are difficult to achieve ideal efficacy. Recent studies have found that CD22 (also known as Siglec-2), as a specific marker of B-cells, is significantly up-regulated on B-cell lymphomas. Inspired by the specific recognition and binding of sialic acid residues by CD22, a polysialic acid (PSA)-modified PLGA nanocarrier (SAPC NP) designed to target B-cell lymphoma was fabricated. Mitoxantrone (MTO) was further loaded into SAPC NP through hydrophobic interactions to obtain polysialylated immunogenic cell death (ICD) nanoinducer (MTO@SAPC NP). Cellular experiments confirmed that MTO@SAPC NP could be specifically taken up by two types of CD22+ B lymphoma cells including Raji and Ramos cells, unlike the poor endocytic performance in other lymphocytes or macrophages. MTO@SAPC NP was determined to enhance the ICD and show better apoptotic effect on CD22+ cells. In the mouse model of B-cell lymphoma, MTO@SAPC NP significantly reduced the systemic side effects of MTO through lymphoma targeting, then achieved enhanced anti-tumor immune response, better tumor suppressive effect, and improved survival rate. Therefore, the polysialylated ICD nanoinducer provides a new strategy for precise therapy of B-cell lymphoma. STATEMENT OF SIGNIFICANCE: • Polysialic acid functionalized nanocarrier (SAPC NP) was designed and prepared. • SAPC NP is specifically endocytosed by two CD22+ B lymphoma cells. • Mitoxantrone-loaded nanoinducer (MTO@SAPC NP) promote immunogenic cell death and anti-tumor immune response. • "Polysialylation" is a potential new approach for precision treatment of B-cell lymphoma.

Erratum: Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis: Erratum.

[This corrects the article DOI: 10.7150/thno.61214.].

Pathological features-based targeted delivery strategies in IBD therapy: A mini review.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by a complex and dysfunctional immune response. Currently, IBD is incurable, and patients with IBD often need to take drugs for life. However, as the traditional systemic treatment strategies for IBD do not target the site of inflammation, only limited efficacy can be obtained from them. Moreover, the possibility of serious side effects stemming from the systemic administration or redistribution of drugs in the body is high when conventional drug formulations are used. Therefore, a targeted drug-delivery system for IBD should be considered. Based on the pathological features related to IBD, the new targeted drug-delivery strategy can directly transfer the drug to the inflammatory site, thus enhancing the accumulation of the drugs and reducing side effects. This article reviews the pathological features of IBD and the application of the IBD-targeted delivery system based on different pathological features, and discusses the challenges and new prospects in this field.

ROS-triggered nanoinducer based on dermatan sulfate enhances immunogenic cell death in melanoma.

Due to its complexity, diversity and heterogeneity, melanoma is a kind of malignant tumor. It has been proved that the enhancement of anti-tumor immune response such as immunogenic cell death (ICD) is an important therapeutic strategy. In previous studies, we confirmed that dermatan sulfate (DS) from skin tissue could specifically homing to melanoma B16F10 cells. In this study, we propose a nanoinducer (DOX/ADS NP) based on a functional DS for melanoma. This nanosystem is composed of DS as framework, aromatic thioketal derivative (ATK) as functional grafting unit and doxorubicin (DOX) designed as an ICD inducer. Through the intermolecular interaction between DOX and ATK, DOX/ADS NP with specific-homing, high-loading and ROS-triggering release was obtained via self-assemble. Compared with free DOX and non-functionalized nanomedicine, DOX/ADS NP could release DOX into B16F10 cells better, and strongly induce the translocation of calreticulin (CRT) to the cell membrane. CRT is a marker of ICD, also as a "eat me" signal to stimulate the maturation and antigen presentation of dendritic cells. Therefore, a series of subsequent immune responses were activated: maturation of dendritic cells, T cells proliferation, increased tumor-infiltrating CTLs and the ratio of CTLs to Tregs, and up-regulated cytotoxic cytokine expression. In conclusion, DOX/ADS NP promoted ICD-associated immune response through more specific targeting effect and sensitive responsive DOX release, achieving better inhibitory effect on melanoma than free DOX and other nanoformulation. This biomimetic ICD nanoinducer based on DS is expected to provide new strategies and references for the treatment of melanoma.

Self-Delivery Janus-Prodrug for Precise Immuno-Chemotherapy of Colitis-Associated Colorectal Cancer.

Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.

Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis.

Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H2O2- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.

Structure of a fucose-rich polysaccharide derived from EPS produced by Kosakonia sp. CCTCC M2018092 and its application in antibacterial film.

A novel exopolysaccharide (EPS) with high molecular weight (3.65 × 105 Da) and film-forming ability was produced by the strain Kosakonia sp. CCTCC M2018092. Partially acid hydrolyzed EPS (AH-EPS) with high content of fucose was prepared and exhaustively characterized. The molecular weight of AH-EPS was determined to be 3.47 × 104 Da. GC-MS and HPLC analyses indicated that AH-EPS is composed of L-fucose, d-glucose, D-galactose, D-glucuronic acid and pyruvic acid in the molar ratio of 2.03:1.00:1.18:0.64:0.67. Chemical and NMR analyses revealed that AH-EPS is an anionic heteropolysaccharide, with a major linkage structural motif as follows. Utilizing AH-EPS as reducing and stabilizing agent, silver nanoparticles (AH-EPS@Ag NPs) with uniform size (diameter about 20 nm) were synthesized through a green method. A hybrid film containing EPS and AH-EPS@Ag NPs was further prepared, and its antibacterial effectiveness to Staphylococcus aureus was confirmed. Taken together, this work revealed the structural characteristics of a novel fucose-rich polysaccharide, with good potential in developing new biodegradable antibacterial film.

A dermatan sulfate-functionalized biomimetic nanocarrier for melanoma targeted chemotherapy.

Melanoma is a malignant tumor of melanocytes that is a serious threat to human health. Dermatan sulfate (DS) is a natural glycosaminoglycan. Inspired by the origin of DS, we report a DS-functionalized biomimetic chitosan nanocarrier (DCNP) for melanoma targeted chemotherapy. DS can anchor to the surface of the chitosan nanocarrier (CNP) by forming amide bond. The SN38/DCNP can rapidly release the anti-tumor drug under acidic conditions. The functionalization of DS not only promoted the specific uptake behavior of melanoma cells, but also up-regulated cleaved caspase-3 and PARP promote tumor cell apoptosis. In vivo model, DCNP reduced the non-specific distribution of SN38 in the circulation and other tissues, while shows superior tumor targeting ability. SN38/DCNP significantly inhibit tumor growth and improved the survival rate. Moreover, SN38/DCNP has a milder myelosuppressive effect. The above results indicated that DS could be used as an excellent targeting unit for the treatment of melanoma.

A self-assembled, ROS-responsive Janus-prodrug for targeted therapy of inflammatory bowel disease.

A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG2K. The morphology of B-ATK-T NP (approximate 100-120nm) was confirmed to be regular spherical by transmission electron microscope. B-ATK-T NP was endowed high drug loading content with 41.23% for Bud and 15.55% for Tem. The rapid drug release from B-ATK-T NP proceeded in an extensive reactive oxygen species (ROS)-dependent manner. More than 98% of Bud and Tem in B-ATK-T NP could release in the mimic inflammation microenvironment or phorbol-12-myristate-13-acetate (PMA)-stimulated macrophages within short time. The release of drugs in a simultaneous and proportional manner ensures that B-ATK-T NP can increase the combined efficacy of anti-inflammation and anti-oxidation. It is worth noting that B-ATK-T NP could be passively accumulated and dramatically increasing the maximum drugs concentration in the inflamed colon of mice with inflammatory bowel disease (IBD) by oral route, and avoiding potential systemic side effects. B-ATK-T NP could not only relieve colitis via inhibiting the expression of oxidative and proinflammatory mediators more than combination of free drugs, but also significantly reduce colitis-caused death. Taken together, the self-assembled, Janus-prodrug B-ATK-T NP is a promising candidate therapies for IBD, even for other inflammatory diseases.