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Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma.

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppre

Bridging the gap: ferroptosis of immune cells in the tumor microenvironment.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a pivotal immunomodulatory mechanism within the tumor microenvironment (TME). Beyond its well-established role in tumor cell elimination, emerging evidence reveals that immune cell subsets exhibit distinct susceptibility to ferroptosis, with profound consequences for antitumor immunity. This review systematically delineates the dual and cell-type-specific roles of ferroptosis across innate and adaptive immune populations: while ferroptosis-mediated depletion of immunosuppress

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… Our advantages include: asialoglycoprotein receptor (ASGPR)-mediated efficient hepatic uptake, pH-responsive drug release for enhanced tumor accumulation, dual-target inhibition (GPX4 and FSP1) to overcome single-pathway resistance, and synergistic chemo-photodynamic therapy with Triapine and Ce6. …

Oleocanthal as a Multifunctional Anti-Cancer Agent: Mechanistic Insights, Advanced Delivery Strategies, and Synergies for Precision Oncology.

Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC's anti-cancer activities, providing an integrative framework to bridge pr

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… G4 PAMAM dendrimers conjugated to N-acetylgalactosamine (GalNAc) can target hepatocytes via the asialoglycoprotein receptor (ASGPR), achieving >90% hepatic uptake. … Hepatocyte targeting can be achieved using nanoparticles functionalized with N-acetylgalactosamine (GalNAc) to exploit asialoglycoprotein receptor (ASGPR) overexpression on hepatocytes. GalNAc-conjugated siRNA therapies (e.g., inclisiran) demonstrate >90% hepatic uptake, a model adaptable to OC. …

A Comprehensive Review of the Management of Light-Chain (AL) and Transthyretin (ATTR) Cardiac Amyloidosis.

Cardiac amyloidosis, once considered a rare and untreatable disorder, is now increasingly recognized as a significant cause of heart failure, particularly in older adults. The two most clinically relevant subtypes of cardiac amyloidosis-immunoglobulin light-chain amyloidosis (AL) and transthyretin-related amyloidosis (ATTR)-differ in pathogenesis, natural history, and management strategies, thereby necessitating a tailored approach to diagnosis and therapy. Advances in multimodality cardiac imaging, including echocardiography, cardiac magnetic resonance, and nuclear scintigraphy, have enabled

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… Its molecular design incorporates phosphorothioate linkages at the 5 ′ end of its siRNA, along with a triantennary N-acetylgalactosamine (GalNAc) ligand, which targets the asialoglycoprotein receptor on hepatocytes. …

8(th) Annual European Antibody Congress 2012: November 27-28, 2012, Geneva, Switzerland.

The 8th European Antibody Congress (EAC), organized by Terrapin Ltd., was again held in Geneva, Switzerland, following on the tradition established with the 4th EAC. The new agenda format for 2012 included three parallel tracks on: (1) naked antibodies; (2) antibody drug conjugates (ADCs); and (3) bispecific antibodies and alternative scaffolds. The meeting started and closed with three plenary lectures to give common background and to share the final panel discussion and conclusions. The two day event included case studies and networking for nearly 250 delegates who learned of the latest adva

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… Data for a molecule composed of interferon-α fused to a liver-specific domain antibody (dAb) recognizing the asialoglycoprotein receptor were presented, including imaging studies with radiolabeled dAbs and fusion proteins, as well as data on efficacy and an improved safety profile in HBV transgenic mice …

Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions.

Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013.

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… OVs were coated with a polygalactosyl-b-agmatyl diblock copolymer (Gal32-b-Agm29), which has a high affinity for the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes [124] . …

Recent Advances in Doxorubicin Formulation to Enhance Pharmacokinetics and Tumor Targeting.

Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanopar

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… FCE28069/PK2 is an HPMA polymer–DOX conjugate linked to a galactosamine structure, which binds to the hepatic asialoglycoprotein receptor. It was designed for treating primary liver cancer. …

Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease.

Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain-derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, whi

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

CAR T therapies in multiple myeloma: unleashing the future.

In recent years, the field of cancer treatment has witnessed remarkable breakthroughs that have revolutionized the landscape of care for cancer patients. While traditional pillars such as surgery, chemotherapy, and radiation therapy have long been available, a cutting-edge therapeutic approach called CAR T-cell therapy has emerged as a game-changer in treating multiple myeloma (MM). This novel treatment method complements options like autologous stem cell transplants and immunomodulatory medications, such as proteasome inhibitors, by utilizing protein complexes or anti-CD38 antibodies with pot

Are RNA Therapies a Solid Foundation or a Frontier Yet to Be Conquered?

The identification of microRNAs (miRNAs) has resulted in significant advancements in research, particularly regarding their utilization as diagnostic and therapeutic targets. This has generated enthusiasm for exploring the potential of non-coding RNAs (ncRNAs) in treating cancer and other diseases, with miRNAs and long non-coding RNAs (lncRNAs) showing particular promise. Over the past twelve years, there has been significant research into RNA-based treatments. Antisense oligonucleotides and small interfering RNAs are the most commonly used. Certain products have received Federal and Drug Admi

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… Oligonucleotides linked to GalNAc, a natural ligand of asialoglycoprotein receptor 1, which is highly expressed in liver cells, are clinically advanced, making them ideal for liver-targeted therapy [ 2 ]. …

Pituitary Adenylate Cyclase-Activating Polypeptide: 30 Years in Research Spotlight and 600 Million Years in Service.

Emerging from the depths of evolution, pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (i.e., PAC1, VPAC1, VPAC2) are present in multicellular organisms from Tunicates to humans and govern a remarkable number of physiological processes. Consequently, the clinical relevance of PACAP systems spans a multifaceted palette that includes more than 40 disorders. We aimed to present the versatility of PACAP1-38 actions with a focus on three aspects: (1) when PACAP1-38 could be a cause of a malfunction, (2) when PACAP1-38 could be the cure for a malfunction, and (3) when PA

Trials and Tribulations of MicroRNA Therapeutics.

The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Cons

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… GalNAc facilitates the targeted delivery of nucleic acid therapeutics through endocytosis by activating liver cell-specific asialoglycoprotein receptors [ 240 , 241 ]. …

RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges.

G protein-coupled receptors (GPCRs) are the major targets of existing drugs for a plethora of human diseases and dominate the pharmaceutical market. However, over 50% of the GPCRs remain undruggable. To pursue a breakthrough and overcome this situation, there is significant clinical research for developing RNA-based drugs specifically targeting GPCRs, but none has been approved so far. RNA therapeutics represent a unique and promising approach to selectively targeting previously undruggable targets, including undruggable GPCRs. However, the development of RNA therapeutics faces significant cha

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… The uncharged nature of the PMO also protects them against biological degradation. 166 , 167 Another method is the covalent attachment of the hepatocyte asialoglycoprotein receptor-binding N-acetylgalactosamine (GalNAc) to the ASOs, siRNAs, miRNAs, and aptamers to achieve gene silencing. 168 , 169 PS …

Целенаправленная деградация белка разрушает ненаркомные цели, чтобы обратить вспять иммунное уклонение и терапию устойчивости к раку.

Таргетированная деградация белков (ТД) использует эндогенные протеолитические системы — систему убиквина и протеасомы и лизосомальные пути — для селективного удаления белков, вызывающих болезни, которые не реагируют на традиционное ингибирование. В онкологической иммунотерапии ТД разрушает критические иммунодепрессивные узлы в экзоцитоплазматическом, мембранном и цитоплазматическом компартментах, перепрограммируя микросреду опухоли от иммунологически «холодной» к «горячей» состоянию. Эта статья рассматривает молекулярные принципы инженерии бифункциональных деградаторов и обобщает клинические д

Engineered mesenchymal stem cell-derived exosomes: A revolutionary approach to unlocking liver disease treatment.

Exosomes, a specific type of extracellular vesicle with diameters ranging from 30 to 150 nm, play a vital role in coordinating various physiological and pathological processes through direct cell-to-cell communication. These vesicles transport a diverse range of molecules, including proteins, mRNAs, miRNAs, and lipids, that originate from parent cells. Exosomes are released by nearly all cell types, including mesenchymal stem cells (MSCs), and possess significant potential due to their regenerative and immunomodulatory properties. In the context of liver disease treatment, these capabilities o

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… This uptake was facilitated by the asialoglycoprotein receptor, which is expressed on HepG2 cells and hepatocytes. When these modified exosomes were injected intravenously into mice with concanavalin A-induced liver injury, they condensed inside the hepatic tissue. …

Advancing CRISPR genome editing into gene therapy clinical trials: progress and future prospects.

Genome editing has recently evolved from a theoretical concept to a powerful and versatile set of tools. The discovery and implementation of CRISPR-Cas9 technology have propelled the field further into a new era. This RNA-guided system allows for specific modification of target genes, offering high accuracy and efficiency. Encouraging results are being announced in clinical trials employed in conditions like sickle cell disease (SCD) and transfusion-dependent beta-thalassaemia (TDT). The path finally led the way to the recent FDA approval of the first gene therapy drug utilising the CRISPR/Cas

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… This system allows access to the LNPs to deliver the drug to liver cells via either the asialoglycoprotein receptor (ASGPR) or the low-density lipoprotein receptor (LDLR). It comprises an adenine base editor-expressing messenger RNA and an optimised RNA targeting PCSK9. …

Резюме АОКНМБ и СНМИКС 2025

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Advances in the delivery of anticancer drugs by nanoparticles and chitosan-based nanoparticles.

Cancer is the leading cause of death globally, and conventional treatments have limited efficacy with severe side effects. The use of nanotechnology has the potential to reduce the side effects of drugs by creating efficient and controlled anticancer drug delivery systems. Nanoparticles (NPs) used as drug carriers offer several advantages, including enhanced drug protection, biodistribution, selectivity and, pharmacokinetics. Therefore, this review is devoted to various organic (lipid, polymeric) as well as inorganic nanoparticles based on different building units and providing a wide range of

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… N -acetylgalactosamine and β-d-galactose are specific ligands for asialoglycoprotein receptors commonly used for targeting liver cancer. Hyaluronic acid (HA) is a widely used ligand for tumor cell-targeting modification, as many tumor cells overexpress CD44 receptors. …

Tumor buster - where will the CAR-T cell therapy 'missile' go?

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME