Delivery of GAS5 by LNP promotes tendon-bone healing in rotator cuff injury.

It is observed in clinical practice that worse healing in rotator cuff tear (RCT) is closely associated with osteoporosis in patients. Herein, from the statistical analysis, we further confirmed that the RCT is significantly increased in postmenopausal women who suffer from decreased bone mineral density (BMD), suggesting intervention of osteoporosis as a potential strategy in the management of RCT in aged women. Our previous studies showed that Growth arrest-specific 5 (GAS5), a long non-coding RNA (lncRNA), could promote bone formation, and alleviate osteoporosis.

Impact of tail unsaturation in ionizable lipids on mRNA delivery efficiency and immunogenicity of lipid nanoparticles.

Ionizable lipids are critical for determining the potency of mRNA lipid nanoparticles (LNPs). Various mRNA therapies require LNPs that achieve efficient delivery while maintaining appropriate immunogenicity in vivo. While research has largely focused on screening the amine headgroups, linkers and hydrophobic tails of ionizable lipids, the role of tail unsaturation in influencing mRNA delivery and immunogenicity of LNPs has received less attention.

Tertiary amine N-oxide zwitterionic lipids facilitate muscle-selective mRNA vaccine delivery for enhancing cDC1-mediated antitumor efficacy.

Lipid nanoparticles (LNPs) have emerged as a groundbreaking platform for delivering messenger RNA (mRNA)-based vaccines and therapeutics. However, clinically approved LNPs administered intramuscularly often lead to unintended liver antigen expression, raising safety concerns related to excessive immune activation and potential tissue damage. Extensive research has focused on optimizing LNPs to adjust their tissue specificity and immunogenicity, while the role of helper lipids as structural components has received little attention.

Cost-effective yet high-performance ionizable lipids for mRNA-lipid nanoparticle vaccines.

Ionizable lipids (ILs) are critical components in mRNA vaccines, which have been instrumental in the global response to SARS-CoV-2. However, current commercialized ILs in mRNA vaccines are typically synthesized through multiple-step organic reactions, complicating quality control and driving up production costs. To address this, we have developed novel ILs by a one-pot Ugi four-component reaction (Ugi-4CR), significantly simplifying synthesis while maintaining high yields and reducing costs.

Exaggerated Lung Inflammation Induced by Lung-Targeted mRNA-LNP Dampens Vaccines against Tuberculosis.

The challenges in developing a tuberculosis (TB) vaccine stem from the complex life cycle of () and various bacterial proteins encoded by approximately 4000 genes. mRNA is easy to design and can accommodate multiple antigens, suggesting that it may be an effective TB vaccine technology. Here, we designed an mRNA encoding Ag85B and ESAT6 that was delivered by lung targeted lipid nanoparticles (LNP-mRNA), intending to stimulate lung immunity to combat TB.

Chemical Design Strategy of Ionizable Lipids for In Vivo mRNA Delivery.

Lipid nanoparticles (LNPs) are the most clinically successful drug delivery systems that have accelerated the development of mRNA drugs and vaccines. Among various structural components of LNPs, more recent attention has been paid in ionizable lipids (ILs) that was supposed as the key component in determining the effectiveness of LNPs for in vivo mRNA delivery. ILs are typically comprised of three moieties including ionizable heads, linkers, and hydrophobic tails, which suggested that the combination of different functional groups in three moieties could produce ILs with diverse chemical structures and biological identities.

Cationic Lipid Pairs Enhance Liver-to-Lung Tropism of Lipid Nanoparticles for In Vivo mRNA Delivery.

Much of current clinical interest has focused on mRNA therapeutics for the treatment of lung-associated diseases, such as infections, genetic disorders, and cancers. However, the safe and efficient delivery of mRNA therapeutics to the lungs, especially to different pulmonary cell types, is still a formidable challenge. In this paper, we proposed a cationic lipid pair (CLP) strategy, which utilized the liver-targeted ionizable lipid and its derived quaternary ammonium lipid as the CLP to improve liver-to-lung tropism of four-component lipid nanoparticles (LNPs) for in vivo mRNA delivery.

A Multidimensional Approach to Modulating Ionizable Lipids for High-Performing and Organ-Selective mRNA Delivery.

The development of lipid nanoparticles (LNPs) has enabled a successful clinical application of mRNA vaccines. However, disclosure of design principles for the core component-ionizable lipids (ILs), improving the delivery efficacy and organ targeting of LNPs, remains a formidable challenge. Herein, we report a powerful strategy to modulate ILs in one-step chemistry using the Ugi four-component reaction (Ugi-4CR) under mild conditions.

Direct Cytosolic Delivery of Proteins and CRISPR-Cas9 Genome Editing by Gemini Amphiphiles via Non-Endocytic Translocation Pathways.

Intracellular delivery of therapeutic biomacromolecules is often challenged by the poor transmembrane and limited endosomal escape. Here, we establish a combinatorial library composed of 150 molecular weight-defined gemini amphiphiles (GAs) to identify the vehicles that facilitate robust cytosolic delivery of proteins in vitro and in vivo. These GAs display similar skeletal structures but differential amphiphilicity by adjusting the length of alkyl tails, type of ionizable cationic heads, and hydrophobicity or hydrophilicity of a spacer.

Effects of adrenergic α-antagonists on the early life stages of Japanese medaka (Oryzias latipes).

The occurrence of pharmaceuticals in the aquatic environment has stimulated considerable research efforts into their potential ecotoxicological consequences. There are a number of pharmaceuticals targeting adrenergic receptors; however, relatively few studies have explored the effects of adrenergic α-antagonists (or α-blockers) on fish. In this study, moxisylyte was selected as a representative α-blocker, and Japanese medaka embryos were exposed to moxisylyte (1-625 μg/L) for 44 days.

Orally administrable polyphenol-based nanoparticles achieve anti-inflammation and antitumor treatment of colon diseases.

Colorectal cancer is the third most common malignancy that leads to significant mortality around the world. Chronic colonic inflammation could induce a protumor effect by the massive release of pro-inflammatory cytokines, facilitating migration, invasion, and metastasis of malignant cells in colorectal cancer. Therefore, developing a combination regimen of anti-inflammation and antitumor therapies is a promising strategy for the treatment of colorectal cancer.

Inhibitory effects of estrogenic endocrine disrupting chemicals on fin regeneration in zebrafish are dependent on estrogen receptors.

For fish and other aquatic organisms, disrupting their capacity for repair and regeneration will reduce their quality of life and survivorship in the wild. Studies have shown that 17α-ethinylestradiol (EE2), a synthetic estrogenic endocrine disrupting chemical (EEDC), can inhibit caudal fin regeneration in larval zebrafish following fin amputation. However, whether the inhibitory effects of EE2 are dependent on estrogen receptor (ER) remains unknown.

Antioxidant Enzymes Sequestered within Lipid-Polymer Hybrid Nanoparticles for the Local Treatment of Inflammatory Bowel Disease.

The local treatment of inflammatory bowel disease (IBD) by enzyme therapeutics is challenging owing to hostile environments in the gastrointestinal tract, leading to the hydrolysis and enzymatic degradation of labile proteins. In this study, safe and efficient local drug delivery systems were developed by antioxidant superoxide dismutase (SOD) sequestered within lipid-polymer hybrid nanoparticles through sequential self-assembly processes. Interestingly, we found that the sequestered SOD exhibited long-term enzymatic stability and comparable biological activity to the enzymes in the native form, probably owing to particle encapsulation providing a physical barrier to prevent the enzymolysis of proteins.

Numerical Analysis of Space Deployable Structure Based on Shape Memory Polymers.

Shape memory polymers (SMPs) have been applied in aerospace engineering as deployable space structures. In this work, the coupled finite element method (FEM) was established based on the generalized Maxwell model and the time-temperature equivalence principle (TTEP). The thermodynamic behavior and shape memory effects of a single-arm deployment structure (F-DS) and four-arm deployment structure (F-DS) based on SMPs were analyzed using the coupled FEM.