Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b+CD45dim microglia population and pro-inflammatory cytokine productions (TNF-α and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors.

OBJECTIVE: microRNA-328 has been reported as a risk factor for myopia development. SHJ002 is an antisense for microRNA-328, and SHJ002 was formulated as ophthalmic solution for a novel microRNA therapy. We aimed to investigate the safety and tolerability of SHJ002 ophthalmic solution in children.
METHODS: This was a single-center, open-label, first-in-human trial in healthy children (NCT04928144). All subjects received the study medication. The trial had 2 stages. Stage 1 was an intrasubject dose-escalation study, and stage 2 was the highest tolerable dose study. The SHJ002 ophthalmic solution was instilled in a randomly selected study eye in each participant, whereas the other untreated eye served as a negative control. Three participants were assigned to stage 1, and they received eye drops of 3 concentrations (0.025%, 0.08%, and 0.25%), each of which was used for 3 consecutive days. The highest tolerable dose from stage 1 was used in stage 2 where another 9 participants were recruited for 28-day treatment. Ocular assessments, physical examination, and vital signs were measured to evaluate safety and tolerability.
RESULTS: There were 4 boys and 8 girls with a mean age of 12.3 years and a SD of 1.56. All participants were Asians. All 3 concentrations used in stage 1 were well tolerated, and the dose of 0.25% was used in stage 2. There were no reports of discomfort. There was only 1 mild adverse event (punctate keratitis) in the untreated eye in 1 participant, which was deemed as \"unrelated to study drug.\"
CONCLUSIONS: SHJ002 is a novel microRNA therapy that uses eye drop instillation. SHJ002 ophthalmic solution is generally safe and tolerable, which warrants further investigations in Phase II and III trials.
RESULTS: gov identifier: NCT04928144.

The effective management of osteomyelitis remains extremely challenging due to the difficulty associated with treating bone defects, the high probability of recurrence, the requirement of secondary surgery or multiple surgeries, and the difficulty in eradicating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Hence, smart biodegradable biomaterials that provide effective and precise local anti-infection effects and can promote the repair of bone defects are actively being developed. Here, a novel nano-micro composite is fabricated by combining calcium phosphate (CaP) nanosheets with drug-loaded GelMA microspheres via microfluidic technology. The microspheres are covalently linked with vancomycin (Van) through an oligonucleotide (oligo) linker using an EDC/NHS carboxyl activator. Accordingly, a smart nano-micro composite called \"CaP@MS-Oligo-Van\" is synthesized. The porous CaP@MS-Oligo-Van composites can target and capture bacteria. They can also release Van in response to the presence of bacterial micrococcal nuclease and Ca2+, exerting additional antibacterial effects and inhibiting the inflammatory response. Finally, the released CaP nanosheets can promote bone tissue repair. Overall, the findings show that a rapid, targeted drug release system based on CaP@MS-Oligo-Van can effectively target bone tissue infections. Hence, this agent holds potential in the clinical treatment of osteomyelitis caused by MRSA.

siRNA therapeutics have gained extensive attention, and to date six siRNAs are approved for clinical use. Despite being investigated for the treatment of metabolic, cardiovascular, infectious, and rare genetic diseases, cancer, and central nervous system (CNS) disorders, there exist several druggability challenges. Here, we provide insightful discussions concerning these challenges, comprising targeted accumulation and cellular uptake (\'entry\'), endolysosomal escape (\'escape\'), and in vivo pharmaceutical performance (\'efficacy\') - the three \'E\' challenges - while also shedding light on siRNA drug development. Moreover, we propose several promising strategies that hold great potential in facilitating the clinical translation of siRNA therapeutics, including the exploration of diverse ligand-siRNA conjugates, expansion of potential disease targets, and excavation of novel modification geometries, as well as the development of combination therapies.

Antimony is highly toxic and a key water pollutant, which needs to be monitored closely. To date, however, most analytical methods for antimony detection are quite limited because they are complicated, expensive, and not suitable for real-time monitoring of antimony. In this study, a label-free and rapid method for antimony ions (Sb3+) detection is developed based on liquid crystals and a 10-mer poly-adenine oligonucleotide as a specific recognition probe for the first time. The working principle is based on the binding of the oligonucleotide to Sb3+, which weakens the interaction between the oligonucleotide and cationic surfactants. As a result, the event induces a planar-to-homeotropic orientational change of liquid crystals and a bright-to-dark optical change under crossed polars. This liquid crystal-based optical sensor exhibits a rapid response to Sb3+ in 10 s, a detection range between 20 nM and 5 μM, and a detection limit at 6.7 nM calculated from 10-mins assay time. It also shows good selectivity against other metal ions including Ag+, Cd2+, Cu2+, Fe3+, K+, Mg2+, Mn2+, Na+, Pb2+, and Zn2+. Moreover, this system can be used to detect Sb3+ in aqueous solutions with different pH or ionic strengths. This simple, fast, and low-cost liquid crystal-based sensing approach with high sensitivity and selectivity has a high potential for detecting Sb3+ in natural environments and industrial wastewater.

Nucleic acid amphiphiles, referring to nucleic acids modified with large hydrophobic groups, have been widely used in programmable bioengineering. Since nucleic acids are intrinsically hydrophilic, the hydrophobic groups endow nucleic acid amphiphiles with unique properties, such as self-assembling, interactions with artificial or biological membranes, and transmembrane transport. Importantly, the hybridization or target binding capability of oligonucleotide itself supplies nucleic acid amphiphiles with excellent programmability. As a result, this type of molecule has attracted considerable attention in academic studies and has enormous potential for further applications. For a comprehensive understanding of nucleic acid amphiphiles, we review the reported research on nucleic acid amphiphiles from their molecular design to final applications, in which we summarize the synthetic strategies for nucleic acid amphiphiles and draw much attention to their unique properties in different contexts. Finally, a summary of the applications of nucleic acid amphiphiles in drug development, bioengineering, and bioanalysis are critically discussed.

Fluorescence in situ hybridization (FISH) provides great conveniences for detection and visualization of specific genomic segments. Oligonucleotide (Oligo)-based FISH further broadened the applications in plant cytogenetics researches. High-specific single-copy oligo probes are essential for successful oligo-FISH experiments. Here, we introduce the bioinformatic pipeline to design genome-scaled single-copy oligos and filter repeat-related probes with Chorus2 software. Robust probes are accessible for both well-assembled genome and species without a reference genome based on this pipeline.

Classically, a molecular element (ME) is a pure substance composed of two or more atoms of the same element. However, MEs, in the context of this review, can be any molecules as elements bonded together into the backbone of synthetic oligonucleotides (ONs) with designed sequences and functions, including natural A, T, C, G, U, and unnatural bases. The use of MEs can facilitate the synthesis of designer molecules and smart materials. In particular, we discuss the landmarks associated with DNA structure and related technologies, as well as the extensive application of ONs, the ideal type of molecules for intervention therapy aimed at correcting disease-causing genetic errors (indels). It is herein concluded that the discovery of ON therapeutics and the fabrication of designer molecules or nanostructures depend on the ME concept that we previously published. Accordingly, ME will be our focal point as we discuss related research directions and perspectives in making molecules and materials. This article is part of the theme issue \'Reactivity and mechanism in chemical and synthetic biology\'.

Oligonucleotides (OGNs) are relatively new modalities that offer unique opportunities to expand the therapeutic targets. Reliable and high-throughput bioanalytical methods are pivotal for preclinical and clinical investigations of therapeutic OGNs. Liquid chromatography-mass spectrometry (LC-MS) is now evolving into being the method of choice for the bioanalysis of OGNs. Ion paring reversed-phase liquid chromatography (IP-RPLC) has been widely used in sample preparation and LC-MS analysis of OGNs; however, there are technical issues associated with these methods. IP-free methods, such as hydrophilic interaction liquid chromatography (HILIC) and anion-exchange techniques, have emerged as promising approaches for the bioanalysis of OGNs. In this review, the state-of-the-art IP-RPLC-MS bioanalytical methods of OGNs and their metabolites published in the past 10 years (2012-2022) are critically reviewed. Recent advances in IP-reagent-free LC-MS bioanalysis methods are discussed. Finally, we describe future opportunities for developing new methods that can be used for the comprehensive bioanalysis of OGNs.

Extracellular vesicles (EVs) are lipid bilayer-delimited particles secreted by cells and are regarded as a promising class of nanocarriers for biomedical applications such as disease diagnosis, drug delivery, and immunomodulation, as they carry biomarkers from the parental cells and can also transport diverse cargo molecules between cells. Surface functionalization of EVs can help obtain detectable signals for their quantification and also add various properties for EV-based delivery. Aptamers are specific oligonucleotides selected as artificial antibodies that could serve as \'cruise missiles\' to target EVs for diagnosis or as navigators to bring EVs to lesions for treatment. DNA logic devices or nanostructures based on aptamers are intelligent designs to endow EVs with additional features, such as multi-target disease diagnosis in one pot and promoting retention of EVs in complex disease microenvironments. Oligonucleotides or DNA nanostructures composed of natural nucleic acids can be easily degraded by nuclease in the biological sample which limits their applications. Thus, the oligonucleotides composed of artificial nucleic acids which are synthesized against degradation would be a potential strategy to improve their stability in vitro or in vivo. Herein, we review the methods for surface functionalization of EVs by nucleic acids and highlight their applications in quantification and targeted delivery towards disease diagnosis and therapy.