Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.

Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an amyotrophic lateral sclerosis mouse model.

Broad-spectrum RNA antiviral inspired by ISG15 deficiency.

Unlabelled: Type I interferons (IFN-I) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of hundreds of IFN-I stimulated genes (ISGs), whose aggregate function results in the control of viral infection. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation.

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Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes.

Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA.

Engineering LNPs with polysarcosine lipids for mRNA delivery.

Since the approval of the lipid nanoparticles (LNP)-mRNA vaccines against the SARS-CoV-2 virus, there has been an increased interest in the delivery of mRNA through LNPs. However, current LNP formulations contain PEG lipids, which can stimulate the generation of anti-PEG antibodies. The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration.

LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing.

Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration.

Biomaterials for in situ cell therapy.

Cell therapy has revolutionized the treatment of various diseases, such as cancers, genetic disorders, and autoimmune diseases. Currently, most cell therapy products rely on ex vivo cell engineering, which requires sophisticated manufacturing processes and poses safety concerns. The implementation of in situ cell therapy holds the potential to overcome the current limitations of cell therapy and provides a broad range of applications and clinical feasibility in the future.

Close the cancer-immunity cycle by integrating lipid nanoparticle-mRNA formulations and dendritic cell therapy.

Effective cancer immunotherapy is usually blocked by immunosuppressive factors in the tumour microenvironment, resulting in tumour promotion, metastasis and recurrence. Here we combine lipid nanoparticle-mRNA formulations and dendritic cell therapy (named CATCH) to boost the cancer-immunity cycle via progressive steps to overcome the immunosuppressive tumour microenvironment. Multiple types of sugar-alcohol-derived lipid nanoparticles are conceived to modulate the cancer-immunity cycle.

Advancements of in vitro transcribed mRNA (IVT mRNA) to enable translation into the clinics.

The accelerated progress and approval of two mRNA-based vaccines to address the SARS-CoV-2 virus were unprecedented. This record-setting feat was made possible through the solid foundation of research on in vitro transcribed mRNA (IVT mRNA) which could be utilized as a therapeutic modality. Through decades of thorough research to overcome barriers to implementation, mRNA-based vaccines or therapeutics offer many advantages to rapidly address a broad range of applications including infectious diseases, cancers, and gene editing.

STING Agonist-Derived LNP-mRNA Vaccine Enhances Protective Immunity Against SARS-CoV-2.

Lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) COVID-19 vaccines has provided large-scale immune protection to the public. To elicit a robust immune response against SARS-CoV-2 infections, antigens produced by mRNAs encoding SARS-CoV-2 Spike glycoprotein need to be efficiently delivered and presented to antigen-presenting cells such as dendritic cells (DCs). As concurrent innate immune stimulation can facilitate the antigen presentation process, a library of non-nucleotide STING agonist-derived amino lipids (SALs) was synthesized and formulated into LNPs for mRNA delivery.

Nanomaterials-Mediated Co-Stimulation of Toll-Like Receptors and CD40 for Antitumor Immunity.

Toll-like receptors (TLRs) and CD40-related signaling pathways represent critical bridges between innate and adaptive immune responses. Here, an immunotherapy regimen that enables co-stimulation of TLR7/8- and CD40-mediated pathways is developed. TLR7/8 agonist resiquimod (R848) derived amino lipids, RAL1 and RAL2, are synthesized and formulated into RAL-derived lipid nanoparticles (RAL-LNPs).

Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.

Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy.

Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy.

Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies.

Delivery of CRISPR-Cas9 system for screening and editing RNA binding proteins in cancer.

RNA-binding proteins (RBPs) play an important role in RNA metabolism, regulating the stability, localization, and functional dynamics of RNAs. Alternation in the RBP-RNA network has profound implications in cellular physiology, and is related to the development and spread of cancer in certain cases. To regulate the expression of specific genes and their biological activities, various strategies have been applied to target RBPs for cancer treatments, including small-molecule inhibitors, small-interfering RNA, peptides, and aptamers.

Construction of Messenger RNA (mRNA) Probes Delivered By Lipid Nanoparticles to Visualize Intracellular Protein Expression and Localization at Organelles.

Organelles are specialized compartments, where various proteins reside and play crucial roles to maintain essential cellular structures and functions in mammalian cells. A comprehensive understanding of protein expressions and subsequent localizations at each organelle is of great benefit to the development of organelle-based therapies. Herein, a set of single or dual organelle labeling messenger RNAs (SOLAR or DOLAR) is designed as novel imaging probes, which encode fluorescent proteins with various organelle localization signals.

Harnessing lipid nanoparticles for efficient CRISPR delivery.

The CRISPR-Cas system has revolutionized the biomedical research field with its simple and flexible genome editing method. In October 2020, Emmanuelle Charpentier and Jennifer A. Doudna were awarded the 2020 Nobel Prize in chemistry in recognition of their outstanding contributions to the discovery of CRISPR-Cas9 genetic scissors, which allow scientists to alter DNA sequences with high precision.

Clinical predictors and risk factors for vaginal mesh extrusion.

Purposes: Our study aims to enhance the accuracy of the clinical diagnosis in patients with vaginal mesh extrusion following transvaginal mesh placement for pelvic organ prolapse using significant clinical parameters and risk factors.

Methods: All patients who underwent vaginal mesh removal were retrospectively reviewed from January 2000 to May 2014. Eligible patients were divided into two groups according to the presence of vaginal mesh extrusion.

The Role of Chronic Mesh Infection in Delayed-Onset Vaginal Mesh Complications or Recurrent Urinary Tract Infections: Results From Explanted Mesh Cultures.

Objectives: Vaginal mesh complications necessitating excision are increasingly prevalent. We aim to study whether subclinical chronically infected mesh contributes to the development of delayed-onset mesh complications or recurrent urinary tract infections (UTIs).

Methods: Women undergoing mesh removal from August 2013 through May 2014 were identified by surgical code for vaginal mesh removal.

Changing Default Fluoroscopy Equipment Settings Decreases Entrance Skin Dose in Patients.

Purpose: Proper fluoroscopic education and protocols may reduce the patient radiation dose but few prospective studies in urology have been performed. Using optically stimulated luminescent dosimeters we tested whether fluoroscopy time and/or entrance skin dose would decrease after educational and radiation reduction protocols.

Materials And Methods: At default manufacturer settings fluoroscopy time and entrance skin dose were prospectively measured using optically stimulated luminescent dosimeters in patients undergoing ureteroscopy, retrograde pyelogram/stent or percutaneous nephrolithotomy with access for stone disease.

Transurethral radiofrequency collagen denaturation for the treatment of women with urinary incontinence.

Background: Transurethral radiofrequency collagen denaturation is a relatively novel, minimally invasive device-based intervention used to treat individuals with urinary incontinence (UI). No systematic review of the evidence supporting its use has been published to date.

Objectives: To evaluate the efficacy of transurethral radiofrequency collagen denaturation, compared with other interventions, in the treatment of women with UI.

A systematic review of the quality of evidence of ablative therapy for small renal masses.

Purpose: We critically assessed the methodological and reporting quality of published studies of ablative techniques for small renal masses.

Materials And Methods: We performed a systematic PubMed® and EMBASE® literature search from January 1966 to March 2010 to identify all full text, original research publications on ablative therapy for renal masses. Six reviewers working independently in 3 teams performed duplicate data abstraction using Strengthening the Reporting of Observational Studies in Epidemiology criteria, which were pilot tested in a separate sample.

Recovery of erectile function after robotic prostatectomy: evidence-based outcomes.

Several reported advantages of the robotic-assisted laparoscopic approach to the treatment of clinically localized prostate cancer include superior results for erectile function as one of the critical outcomes of radical prostate surgery. This article provides a critical assessment of the evidence that exists for erectile function outcomes based on a systematic literature review. We found that the low methodological and reporting quality of existing studies did not appear well suited to guide clinical practice.

Low quality of evidence for robot-assisted laparoscopic prostatectomy: results of a systematic review of the published literature.

Background: Robot-assisted laparoscopic prostatectomy (RALP) is displacing radical retropubic prostatectomy as the gold standard surgical approach for clinically localised prostate cancer in the United States and is also being increasingly used in Europe and other parts of the world. This trend has occurred despite the paucity of high-quality evidence to support its relative superiority to more established treatment modalities.

Objective: We performed this study to critically assess the quality of published evidence on RALP to support this major shift in practice patterns.