Lipid Nanoparticles Formulated with a Novel Cholesterol-Tailed Ionizable Lipid Markedly Increase mRNA Delivery Both in vitro and in vivo.

Background: Lipid nanoparticles (LNPs) have emerged as the most successful, effective, and safe method for RNA delivery, and have shown tremendous potential for the treatment of various diseases, such as messenger RNA (mRNA) vaccines, gene editing, and RNA interface (RNAi) therapies. The development of novel ionizable lipids holds great promise in improving the efficacy and safety of LNPs.

Methods: We synthesized a novel ionizable lipid, ARV-T1, with a cholesterol moiety incorporated in its tail.

Membrane Expression Enhances Folding, Multimeric Structure Formation, and Immunogenicity of Viral Capsid Proteins.

Viral capsid proteins are widely explored for subunit vaccine development but are often hampered by their complexity of production and low immunogenicity. Here, we report a simple approach to overcoming these challenges by combining mRNA vaccine technology with protein engineering. Using African swine fever virus (ASFV) capsid proteins P72 and penton as models, we engineered them into membrane-bound and secreted forms and compared their immunogenicity to that of the native intracellular form in mice and pigs through mRNA vaccination.

Engineering myeloid cells for cancer immunotherapy.

Macrophages naturally infiltrate tumors, modulate tumor microenvironment, phagocytose tumor cells, and present antigens to induce T cell responses. These properties have been leveraged to develop chimeric antigen receptor-macrophages (CAR-Ms) for cancer immunotherapy. We discuss key findings from CAR-M studies to assess their potential to overcome major limitations of current CAR-T cell therapies and outline research directions to optimize CAR-Ms as a safe, efficacious, and cost-effective cancer immunotherapy.

Selection, Design, and Immunogenicity Studies of ASFV Antigens for Subunit mRNA Cocktail Vaccines with Specific Immune Response Profiles.

Development of safe and effective subunit vaccines for controlling African Swine Fever Virus (ASFV) infection has been hampered by a lack of protective viral antigens, complex virion structures, and multiple mechanisms of infection. Here, we selected ASFV antigens based on their localization on the virion, known functions, and homologies to the subunits of the protective vaccinia virus vaccine. We also engineered viral capsid proteins for inducing optimal antibody responses and designed T cell-directed antigens for inducing broad and robust cellular immunity.

Selection, Design and Immunogenicity Studies of ASFV Antigens for Subunit mRNA Cocktail Vaccines with Specific Immune Response Profiles.

Development of safe and effective subunit vaccines for controlling African Swine Fever Virus (ASFV) infection has been hampered by a lack of protective viral antigens, complex virion structures, and multiple mechanisms of infection. Here, we selected ASFV antigens based on their localization on the virion, known functions, and homologies to the subunits of the protective vaccinia virus vaccine. We also engineered viral capsid proteins for inducing optimal antibody responses and designed T cell-directed antigen for inducing broad and robust cellular immunity.

Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses.

The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli (E. coli) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E.

Adhesive anti-fibrotic interfaces on diverse organs.

Implanted biomaterials and devices face compromised functionality and efficacy in the long term owing to foreign body reactions and subsequent formation of fibrous capsules at the implant-tissue interfaces. Here we demonstrate that an adhesive implant-tissue interface can mitigate fibrous capsule formation in diverse animal models, including rats, mice, humanized mice and pigs, by reducing the level of infiltration of inflammatory cells into the adhesive implant-tissue interface compared to the non-adhesive implant-tissue interface. Histological analysis shows that the adhesive implant-tissue interface does not form observable fibrous capsules on diverse organs, including the abdominal wall, colon, stomach, lung and heart, over 12 weeks in vivo.

Bosutinib Stimulates Macrophage Survival, Phagocytosis, and Intracellular Killing of Bacteria.

Host-acting compounds are emerging as potential alternatives to combating antibiotic resistance. Here, we show that bosutinib, an FDA-approved chemotherapeutic for treating chronic myelogenous leukemia, does not possess any antibiotic activity but enhances macrophage responses to bacterial infection. In vitro, bosutinib stimulates murine and human macrophages to kill bacteria more effectively.

Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis.

Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms remain unclear. Here, we show that activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells stimulates glycolysis and protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcription of glycolytic genes.

Pharmacological functions of salidroside in renal diseases: facts and perspectives.

is a valuable functional medicinal plant widely utilized in China and other Asian countries for its anti-fatigue, anti-aging, and altitude sickness prevention properties. Salidroside, a most active constituent derived from , exhibits potent antioxidative, hypoxia-resistant, anti-inflammatory, anticancer, and anti-aging effects that have garnered significant attention. The appreciation of the pharmacological role of salidroside has burgeoned over the last decade, making it a beneficial option for the prevention and treatment of multiple diseases, including atherosclerosis, Alzheimer's disease, Parkinson's disease, cardiovascular disease, and more.

Si-enriched biochars improved soil properties, reduced Cd bioavailability while enhanced Cd translocation to grains of rice.

Biochar and silicon (Si) have been widely considered to play an important role in mitigating cadmium (Cd) toxicity. In this study, wild-type rice (WT, high-Si) and Si-deficient mutant rice (lsi1, low-Si) were used as raw materials to prepare biochar at 500℃; the Si concentrations of high- and low-Si biochar were 15.9% and 5.

Monovalent SARS-COV-2 mRNA vaccine using optimal UTRs and LNPs is highly immunogenic and broadly protective against Omicron variants.

The emergence of highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that are resistant to the current COVID-19 vaccines highlights the need for continued development of broadly protective vaccines for the future. Here, we developed two messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, TU88mCSA and ALCmCSA, using the ancestral SARS-CoV-2 spike sequence, optimized 5' and 3' untranslated regions (UTRs), and LNP combinations. Our data showed that these nanocomplexes effectively activate CD4 and CD8 T cell responses and humoral immune response and provide complete protection against WA1/2020, Omicron BA.

IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy.

Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation.

Mitoxantrone targets both host and bacteria to overcome vancomycin resistance in .

Antibiotic resistance critically limits treatment options for infection caused by opportunistic pathogens such as enterococci. Here, we investigate the antibiotic and immunological activity of the anticancer agent mitoxantrone (MTX) in vitro and in vivo against vancomycin-resistant (VRE). We show that, in vitro, MTX is a potent antibiotic against Gram-positive bacteria through induction of reactive oxygen species and DNA damage.

Selective expression of variant surface antigens enables Plasmodium falciparum to evade immune clearance in vivo.

Plasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth.

Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML.

Ovarian Cancer Ascites Inhibits Transcriptional Activation of NK Cells Partly through CA125.

Malignant ascites is a common clinical problem in ovarian cancer. NK cells are present in the ascites, but their antitumor activity is inhibited. The underlying mechanisms of the inhibition have yet to be fully elucidated.

Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines.

Dengue is the most common arboviral disease caused by one of four distinct but closely related dengue viruses (DENV) and places significant economic and public health burdens in the endemic areas. A dengue vaccine will be important in advancing disease control. However, the effort has been challenged by the requirement to induce effective protection against all four DENV serotypes and the potential adverse effect due to the phenomenon that partial immunity to DENV may worsen the symptoms upon subsequent heterotypic infection.

Current Developments and Challenges of mRNA Vaccines.

mRNA vaccines have brought about a great revolution in the vaccine fields owing to their simplicity and adaptability in antigen design, potential to induce both humoral and cell-mediated immune responses and demonstrated high efficacy, and rapid and low-cost production by using the same manufacturing platform for different mRNA vaccines. Multiple mRNA vaccines have been investigated for both infectious diseases and cancers, showing significant superiority to other types of vaccines. Although great success of mRNA vaccines has been achieved in the control of the coronavirus disease 2019 pandemic, there are still multiple challenges for the future development of mRNA vaccines.

In Vitro Engineering Chimeric Antigen Receptor Macrophages and T Cells by Lipid Nanoparticle-Mediated mRNA Delivery.

Chimeric antigen receptor (CAR)-engineered adoptive cell therapy marks a revolution in cancer treatment based on the highly successful responses to CAR T cell therapy in the treatment of blood cancers. Due to the versatile structure of CARs, this technology can be easily adapted to other immune cell types, including macrophages and NKs, and applied in the treatment of many other cancers. However, high costs and fatal adverse effects represent significant concerns for future development.

In situ cancer vaccination using lipidoid nanoparticles.

In situ vaccination is a promising strategy for cancer immunotherapy owing to its convenience and the ability to induce numerous tumor antigens. However, the advancement of in situ vaccination techniques has been hindered by low cross-presentation of tumor antigens and the immunosuppressive tumor microenvironment. To balance the safety and efficacy of in situ vaccination, we designed a lipidoid nanoparticle (LNP) to achieve simultaneously enhancing cross-presentation and STING activation.