RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO ® (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.

Suffering from the laborious synthesis and undesirable tumor microenvironment response,t he exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy.Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly.Because of the larger energy gap between donor and acceptor,T MB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates.T herefore,T MB-F4TCNQ exhibits stronger NIR-II absorption ability with am ass extinction coefficient of 15.4 Lg À1 cm À1 at 1300 nm and excellent photothermal effect. Impressively,the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redoxd syhomeostasis and ROS-mediated ferroptosis.T MB-F4TCNQ can serve as ac ontrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapyinv ivo.

Prostaglandin F 2 ␣ (PGF 2 ␣) binding to its receptor on the rat corpus luteum triggers various signal transduction pathways that lead to the activation of a steroidogenic enzyme, 20␣-hydroxysteroid dehydrogenase (20␣-HSD), which in turn catabolizes progesterone. The molecular mechanism underlying PGF 2 ␣-induced 20␣-HSD enzyme activity has not yet been explored. In this report we show, using mice lacking PGF 2 ␣ receptor and pregnant rats, that PGF 2 ␣ is responsible for the rapid and massive expression of the 20␣-HSD gene at the end of pregnancy leading to a decrease in progesterone secretion. We also present evidence that PGF 2 ␣ enhances 20␣-HSD promoter activity. We have determined a region upstream of the ؊1590 position in the 20␣-HSD promoter that confers regulation by PGF 2 ␣ in ovarian primary cells. This region encompasses a unique transcription factor-binding site with a sequence of a NUR77 response element. Deletion of this motif or overexpression of a NUR77 dominant negative protein caused a complete loss of 20␣-HSD promoter activation by PGF 2 ␣. NUR77 also transactivated the 20␣-HSD promoter in transient transfection experiments in corpus luteumderived cells (GG-CL). This induction required the NUR77-transactivating domain. We also show that PGF 2 ␣ induces a very rapid expression of NUR77 that binds to a distal response element located at ؊1599/ ؊1606 but does not interact with another proximal putative NUR77 response element located downstream in the promoter. A rapid increase in NUR77 mRNA was observed in mice corpora lutea just before parturition at a time when 20␣-HSD becomes expressed. This increase in the expression of both genes was not seen in PGF 2 ␣ receptor knockout mice. By using cyclosporin A and PGF 2 ␣ treatment, we established that inhibition of NUR77 DNA binding in vivo prevents PGF 2 ␣ induction of the 20␣-HSD gene in the corpus luteum. Taken together, our results demonstrate, for the first time, that PGF 2 ␣ induces in the corpus luteum the expression of the nuclear orphan receptor and transcription factor, NUR77, which in turn leads to the transcriptional stimulation of 20␣-HSD, triggering the decrease in serum progesterone essential for parturition.In all mammalian species, progesterone plays an essential role in reproduction. The precise timing of both the synthesis and degradation of this steroid hormone is crucial for reproductive success. The expression of enzymes implicated in the synthesis and catabolism of progesterone, therefore, needs to be accurately regulated during the different reproductive states of the animal. In rodents, the corpus luteum, which is the only source of progesterone throughout pregnancy (1), is also able to express the enzyme 20␣-hydroxysteroid dehydrogenase (20␣-HSD)1 that converts progesterone into a biologically inactive steroid, thus playing a key role in the termination of pregnancy and allowing parturition to occur (2). Due to the detrimental effect of 20␣-HSD on luteal progesterone secretion, the corpus luteum of pregnancy does not express...

The current feasibility of nanocatalysts in clinical anti-infection therapy, especially for drug-resistant bacteria infection is extremely restrained because of the insufficient reactive oxygen generation. Herein, a novel Ag/Bi2MoO6 (Ag/BMO) nanozyme optimized by charge separation engineering with photoactivated sustainable peroxidase-mimicking activities and NIR-II photodynamic performance was synthesized by solvothermal reaction and photoreduction. The Ag/BMO nanozyme held satisfactory bactericidal performance against methicillin-resistant Staphylococcus aureus (MRSA) (~99.9%). The excellent antibacterial performance of Ag/BMO NPs was ascribed to the corporation of peroxidase-like activity, NIR-II photodynamic behavior, and acidity-enhanced release of Ag+. As revealed by theoretical calculations, the introduction of Ag to BMO made it easier to separate photo-triggered electron-hole pairs for ROS production. And the conduction and valence band potentials of Ag/BMO NPs were favorable for the reduction of O2 to ·O2−. Under 1064 nm laser irradiation, the electron transfer to BMO was beneficial to the reversible change of Mo5+/Mo6+, further improving the peroxidase-like catalytic activity and NIR-II photodynamic performance based on the Russell mechanism. In vivo, the Ag/BMO NPs exhibited promising therapeutic effects towards MRSA-infected wounds. This study enriches the nanozyme research and proves that nanozymes can be rationally optimized by charge separation engineering strategy.

AMP-activated protein kinase (AMPK), known as a sensor and a master of cellular energy balance, integrates various regulatory signals including anabolic and catabolic metabolic processes. Accompanying the application of genetic methods and a plethora of AMPK agonists, rapid progress has identified AMPK as an attractive therapeutic target for several human diseases, such as cancer, type 2 diabetes, atherosclerosis, myocardial ischemia/reperfusion injury and neurodegenerative disease. The role of AMPK in metabolic and energetic modulation both at the intracellular and whole body levels has been reviewed elsewhere. In the present review, we summarize and update the paradoxical role of AMPK implicated in the diseases mentioned above and put forward the challenge encountered. Thus it will be expected to provide important clues for exploring rational methods of intervention in human diseases.