Ångstrom-scale gold particles loaded with alendronate via alpha-lipoic acid alleviate bone loss in osteoporotic mice.

Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.

In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy.

In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.

Biofunctional coacervate-based artificial protocells with membrane-like and cytoplasm-like structures for the treatment of persistent hyperuricemia.

Coacervate droplets formed by liquid-liquid phase separation have attracted considerable attention due to their ability to enrich biomacromolecules while preserving their bioactivities. However, there are challenges to develop coacervate droplets as delivery vesicles for therapeutics resulting from the lack of physiological stability and inherent lack of membranes in coacervate droplets. Herein, polylysine-polynucleotide complex coacervate droplets with favorable physiological stability are formulated to efficiently and facilely concentrate small molecules, biomacromolecules and nanoparticles without organic solvents. To improve the biocompatibility, the PEGylated phospholipid membrane is further coated on the surface of the coacervate droplets to prepare coacervate-based artificial protocells (ArtPC) with membrane-like and cytoplasm-like structures. The ArtPC can confine the cyclic catalytic system of uricase and catalase inside to degrade uric acid and deplete the toxicity of H2O2. This biofunctional ArtPC effectively reduces blood uric acid levels and prevents renal injuries in mice with persistent hyperuricemia. The ArtPC-based therapy can bridge the disciplines of synthetic biology, pharmaceutics and therapeutics.

Yeast Microcapsule Mediated Natural Products Delivery for Treating Ulcerative Colitis through Anti-Inflammatory and Regulation of Macrophage Polarization.

The common and frequent disease, ulcerative colitis (UC), causes serious physical and mental distress to patients. M2 macrophages have proven to play a role in anti-inflammation, which is a new potential target for UC therapy. In this study, we designed a safe and macrophages-targeting oral drug delivery system. Natural products, berberine (BBR), and Epigallocatechin Gallate (EGCG) with anti-inflammatory activity were assembled and encapsulated into yeast microcapsule (YM), generating therapeutic system BBR/MPN@YM. BBR and EGCG exhibited synergistic effects against UC through the effect of antioxidation. Through the interaction between ß-1,3-d-glucan on the surface of YM and dectin-1 receptors on macrophages, BBR/MPN@YM could be effectively transported to inflammation parts and internalized into macrophages, avoiding gastric degradation. In the in vivo UC mouse model, BBR/MPN@YM could transform M1 macrophages into anti-inflammatory M2 macrophages, thus exerting specific anti-inflammatory effects. Therefore, this BBR/MPN@YM targeted oral drug delivery system provided a new macrophages-targeting strategy for the clinical treatment of UC.

Palladium and Brønsted Acid Co-Catalyzed Biginelli-like Multicomponent Reactions via in Situ-Generated Cyclic Enol Ether: Access to Spirofuran-hydropyrimidinones.

Alkynol served as an enolizable carbonyl equivalent to react with (thio)urea and aromatic aldehydes, furnishing a variety of spirofuran-hydropyrimidinone compounds in good yields and excellent diastereoselectivities. The one-pot multicomponent reactions were realized with co-catalysis of palladium chloride and trifluoroacetic acid through a Biginelli-like tandem reaction pathway.

Transition metal/Brønsted acid cooperative catalysis enabled facile synthesis of 8-hydroxyquinolines through one-pot reactions of ortho-aminophenol, aldehydes and alkynes.

A convenient and straightforward three-component one-pot strategy has been developed for the synthesis of 8-hydroxyquinoline derivatives. Under the cooperative catalysis of silver(i) triflate and trifluoroacetic acid, ortho-aminophenol reacted with a range of aldehydes and alkynes under mild reactions, affording the corresponding 8-hydroxyquinoline derivatives with good to excellent yields. These transformations exhibited exceptional substrate generality and functional group compatibility.