: As a key mechanism of metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, inflammation triggered by chronic liver injury and immune cells with macrophages enables MASLD to progress to an advanced stage with irreversible processes such as fibrosis, cell necrosis, and cancer in the liver. The complexity of MASLD, including crosstalk between multiple organs and the liver, makes developing a new drug for MASLD challenging, especially in single-drug therapy. It was reported that upregulation of Notch1 is closely associated with the function of pro-inflammatory macrophages.
View Article and Find Full Text PDFLiver fibrosis, a hallmark of chronic liver diseases, is characterized by excessive extracellular matrix (ECM) deposition and scar tissue formation. Current antifibrotic nanomedicines face significant limitations, including poor penetration into fibrotic tissue, rapid clearance, and suboptimal therapeutic efficacy. The dense fibrotic ECM acts as a major physiological barrier, necessitating the development of a targeted delivery strategy to achieve effective therapeutic outcomes.
View Article and Find Full Text PDFTumor hypoxia is a critical driver of cancer progression, metastasis, and therapy resistance, posing significant challenges in effective cancer treatment. Hypoxia-activable prodrugs offer a promising strategy to target tumors in low-oxygen conditions, but their efficacy is often hindered by intrinsic properties and extrinsic cues. In this study, we developed a dual-prodrug nanoassembly system (CPPA) composed of a hypoxia-triggerable camptothecin (CPT)-based dimeric prodrug (CP) and a lipid-conjugated STAT3 antisense oligonucleotide (ASO) prodrug (PA), aiming to enhance tumor-targeted chemotherapy and overcome the immune evasion within the tumor microenvironment.
View Article and Find Full Text PDFThe cGAS-STING axis is a promising therapeutic target against cancer. However, most activators require STING signaling in the host, especially within antigen-presenting cells, which are rare in a cold tumor microenvironment. The cGAS-STING cascade is also present within cancer cells but with suppressed activity.
View Article and Find Full Text PDFPsoriatic self-antigen LL37 has the ability to stimulate skin-homing T lymphocytes, which is the constitutive factor for the relapse of psoriasis. The local inflammatory modulation in psoriatic skin is not sufficient for the restoration of immune homeostasis. In this study, we found the expression levels of disease specific proteins including LL37, S100A8 and S100A9 were significantly increased in psoriasis.
View Article and Find Full Text PDFLipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway.
View Article and Find Full Text PDFCancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC).
View Article and Find Full Text PDFInflammation-related diseases impose a significant global health burden, necessitating urgent exploration of novel treatment modalities for improved clinical outcomes. We begin by discussing the limitations of conventional approaches and underscore the pivotal involvement of immune cells in the inflammatory process. Amidst the rapid growth of immunology, the therapeutic potential of immune cell-derived extracellular vesicles (EVs) has garnered substantial attention due to their capacity to modulate inflammatory response.
View Article and Find Full Text PDFThe poor permeability of therapeutic drugs, limited T-cell infiltration, and strong immunosuppressive tumor microenvironment of triple-negative breast cancer (TNBC) acts as a prominent barrier to the delivery of drugs and immunotherapy including programmed cell death ligand-1 antibody (anti-PD-L1). Transforming growth factor (TGF)-β, an important cytokine produced by cancer-associated fibroblasts (CAFs) and tumor cells contributes to the pathological vasculature, dense tumor stroma and strong immunosuppressive tumor microenvironment (TME). Herein, a nanomedicine platform (HA-LSL/siTGF-β) employing dual-targeting, alongside hyaluronidase (HAase) and glutathione (GSH) triggered release was elaborately constructed to efficiently deliver TGF-β small interference RNA (siTGF-β).
View Article and Find Full Text PDFNon-alcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease characterized by "multiple crosstalk" paths of insulin resistance, lipid metabolism, oxidative stress, . The combination of LY294002 and oridonin was proposed as a promising therapy by targeting insulin-PI3K/AKT signaling and NF-κB inflammatory pathway. However, due to oxidative stress, disease-associated upregulation of murine CYP3A11 activity can contribute to unexpected drug metabolism and disposition, which could seriously hinder the efficacy of LY294002 and oridonin.
View Article and Find Full Text PDFFerroptosis has been proposed as one form of iron-dependent cell death, overgeneration of high-toxicity hydroxyl radicals (˙OH) tumor sites Fenton reactions induced cell membrane damage. However, the insufficient intracellular concentrations of both iron and HO limited the anticancer performance of ferroptosis. In this study, ROS-sensitive prodrug nanoassemblies composed of a PEG2000-ferrous compound and a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug were constructed, which fully tapped ex/endogenous iron, ferroptosis inducers, and chemotherapeutic agents.
View Article and Find Full Text PDFPurpose: Oxidative stress, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and adenosine signaling are factors associated with psoriatic inflammation. Topical delivery of methotrexate (MTX) has become an option to overcome the side effects caused by systemic therapy in psoriasis, leading to the suppression of NF-κB activation through boosting adenosine release. However, thickened psoriatic skin is the primary restriction against local drug delivery.
View Article and Find Full Text PDFThe interplay of liposome-protein corona hinders the clinical application of liposomes due to active macrophage sequestration and rapid plasma clearance. Here we showed that, CXCL10 as a therapeutic protein was coronated the thermosensitive liposomes to form stealth-like nanocarriers (CXCL10/TSLs). Decoration of the corona layer of CXCL10/TSLs by hyaluronic acid conjugated oridonin (ORD/CXCL10/TSLs), overcame the "fluid barrier" built by biological proteins, drastically reduced capture by leukocytes in whole blood, allowed the specific targeting of tumor sites.
View Article and Find Full Text PDFDespite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-β) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines.
View Article and Find Full Text PDFThe co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor.
View Article and Find Full Text PDFThe full-length AU-rich (63.14%) 2,794-nucleotide sequence of Rhizoctonia mitovirus K1 (RMV-K1) isolated from the binucleate AG-K strain FAS2909W was determined. The positive strand of RMV-K1 contains a large open reading frame (ORF) when the fungal mitochondrial genetic code is used.
View Article and Find Full Text PDFHepatic fibrosis remains a serious threat to human health globally and there are no effective antifibrotic pharmacotherapeutic strategies, to date. Upon the activation of hepatic stellate cells, excess deposition of the extracellular matrix occurs, acting as a trigger that generates reactive oxygen species and an inflammatory response, thereby exacerbating the development of hepatic fibrosis and inflammation. In this study, we incorporated an idea that targets key pathways for developing novel anti-fibrosis nanomedicine.
View Article and Find Full Text PDFCo-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy.
View Article and Find Full Text PDFStrong infectivity enables coronavirus disease 2019 (COVID-19) to rage throughout the world. Moreover, the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic. Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs.
View Article and Find Full Text PDFInvasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance.
View Article and Find Full Text PDFCrit Rev Ther Drug Carrier Syst
June 2021
Multidrug resistance (MDR) remains a major obstacle to ensure effective chemotherapy in cancer patients. Several factors could be associated with cancer cells' drug resistance such as overexpression of P-glycoprotein (P-gp), cancer stem cells (CSCs), defect in apoptosis, mutation and alteration in DNA repair pathways, angiogenesis, autophagy, and modulation in metabolic enzymes. Until now, drug efflux by ABC transporters has been a univocal and well-established mechanism of chemotherapeutic associated drug resistance.
View Article and Find Full Text PDFCancer-associated fibroblasts (CAFs) are the majority cell population of tumor stroma, and they not only play important roles in tumor growth and metastasis, but they also form a protective physical barrier for cancer cells. Herein, we designed a fibroblast activation protein-α (FAP-α)-adaptive polymeric micelle based on hyaluronic acid and curcumin conjugates. The polymeric micelle is composed of a CD44-targeting shell and a FAP-α-cleavable polyethylene glycol (PEG) coating.
View Article and Find Full Text PDFDuring the process of cancer metastasis, various enzymes, cytokines, and factors were involved, and upregulated cyclooxygenase-2(COX-2) in tumor cells led to proliferation and invasion of various tumors. Many nonsteroidal anti-inflammatory drugs (NSAIDs) were used as an anticancer adjuvant in chemotherapy, such as ibuprofen (BF) and celecoxib. NSAIDs could effectively inhibit local inflammation and decreased COX-2 expression.
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