Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo.

Nucleic acid therapeutics offer tremendous promise for addressing a wide range of common public health conditions. However, the in vivo nucleic acids delivery faces significant biological challenges. Lipid nanoparticles (LNPs) possess several advantages, such as simple preparation, high stability, efficient cellular uptake, endosome escape capabilities, etc., making them suitable for delivery vectors. However, the extensive hepatic accumulation of LNPs poses a challenge for successful development of LNPs-based nucleic acid therapeutics for extrahepatic diseases. To overcome this hurdle, researchers have been focusing on modifying the surface properties of LNPs to achieve precise delivery. The review aims to provide current insights into strategies for LNPs-based organ-selective nucleic acid delivery. In addition, it delves into the general design principles, targeting mechanisms, and clinical development of organ-selective LNPs. In conclusion, this review provides a comprehensive overview to provide guidance and valuable insights for further research and development of organ-selective nucleic acid delivery systems.

Dietary cobalt oxide nanoparticles alleviate aging through activation of mitochondrial UPR in Caenorhabditis elegans.

Mitochondrial unfolded protein response (UPRmt), which is a mitochondrial proteostasis pathway, orchestrates an adaptive reprogramming for metabolism homeostasis and organismal longevity. Similar to other defense systems, compromised UPRmt is a feature of several age-related diseases. Here we report that dimercapto succinic acid (DMSA)-modified cobalt oxide nanoparticles (Co3O4 NPs), which have received wide-spread attention in biomedical fields, is a promising UPRmt activator and, more importantly, provides a gate for extending healthy lifespan. Methods: UPRmt activation by Co3O4 NPs was tested in transgenetic Caenorhabditis elegans (C. elegans) specifically expressing UPRmt reporter Phsp-6::GFP, and the underlying mechanism was further validated by mitochondrial morphology, mtDNA/nDNA, metabolism-related genes' expression, mitonuclear protein imbalance, oyxgen assumption and ATP level in C. elegans. Then therapeutic response aganist senescence was monitored by lifespan analysis, lipofusin contents, MDA contents, Fe accumulation, pharyngeal locomotion performance as well as athletic ability (head thrashes and body bends) at different developmental stages of C. elegans. RNAi towards ubl-5 or atfs-1 in UPRmt pathway was applied to clarify the role of UPRmt in Co3O4 NPs -mediated anti-aging effects. Finally, the effect of Co3O4 NPs on mitochondrial homeostasis and D-galactose-induced cell viability decline in mammalian cells were studied. Results: Co3O4 NPs was revealed as a bona fide activator of the UPRmt signaling pathway, through fine-tuning mitochondrial dynamics and inducing a stoichiometric imbalance between OXPHOS subunits encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) at early life stage of C. elegans. Phenotypically, Co3O4 NPs treatment protect C. elegans from external stresses. More importantly, dietary low level of Co3O4 NPs effectively extend lifespan and alleviate aging-related physiological and functional decline of worms, demonstrating its potential roles in delaying aging. While the protective effect exerted by Co3O4 NPs was compromised in line with atfs-1 or ubl-5 RNAi treatment. Further studies verified the conservation of Co3O4 NPs in activating UPRmt and exerting protective effects in mammalian cells. Conclusions: The results reveal beneficial effects of Co3O4 NPs on mitochondrial metabolic control, thus presenting their potential efficacy in anti-aging care.

Selection and Identification of an ssDNA Aptamer for Fibroblast Activation Protein.

As a type II transmembrane serine protease, fibroblast activation protein (FAP) is specifically expressed on the surface of fibroblasts associated with a variety of epithelial-derived malignancies such as pancreatic cancer, breast cancer, and colon cancer. It participates in the processes of tumorigenesis, progression, and immunosuppression. FAP constitutes an important target for tumor treatment; however, the current studies on FAP are mainly related to structural characteristics, enzymatic properties, and biological functions, and aptamers of FAP have not been investigated. In this work, by using recombinant human FAP as the target, five candidate aptamers, which are AptFAP-A1, AptFAP-A2, AptFAP-A3, AptFAP-A4, and AptFAP-A5, were selected by capillary electrophoresis-systematic evolution of ligands by exponential enrichment (CE-SELEX), and their secondary structures were predicted to be mainly stem-loop. Moreover, the CE-laser-induced fluorescence (LIF) method was used to determine the equilibrium dissociation constant KD values between the FAP protein and candidate aptamers, and the KD value was in the low molar range. Finally, Cy5-labeled aptamers were co-incubated with human pancreatic cancer-associated fibroblasts highly expressing FAP protein, and confocal microscopy imaging showed that aptamer AptFAP-A4 had the highest affinities with the cells. The FAP aptamers screened in this study provide a promising direction for the development of rapid tumor diagnosis and targeted therapy.

Activation of KLF6 by titanate nanofibers and regulatory roles of KLF6 on ATF3 in the endothelial monolayer and mouse aortas.

Although titanium (Ti)-based nanomaterials (NMs) were traditionally considered as biologically inert materials, it was recently reported that Ti-based NMs induce adverse vascular effects by inhibiting Kruppel-like factor 2 (KLF2) and/or KLF4, vasoprotective KLFs with well-documented regulatory activity in NO signaling. However, the potential roles of other KLFs are not clear. KLF6 was recently identified as an important KLF involved in regulating endothelial dysfunction, inflammation, and angiogenesis, therefore, this study investigated the influence of titanate nanofibers (TiNFs) on KLF6-mediated events. Ingenuity pathway analysis (IPA) showed that TiNFs altered the expression of a panel of KLF6-related genes: KLF6-mediated gene ontology (GO) terms were altered, categories including cytokine-mediated signaling pathways, transcription factor (TF) functions and membrane-bound organelles. Additionally, RT-PCR confirmed that TiNFs increased KLF6 activating transcription factor 3 (ATF3), a TF involved in endoplasmic reticulum (ER) stress, and ELISA confirmed the increase of soluble monocyte chemotactic protein 1 (sMCP-1), a KLF6-related inflammatory cytokine. Interestingly, the activation of klf6, atf3 and C-C motif chemokine ligand 2 (ccl2; mcp-1 encoding gene) was observed in aortas of mice following one-time intravenous injection but not intratracheal instillation of TiNFs (100 µg per mouse), indicating a need for direct contact with NMs to activate klf6-mediated pathways in vivo. In endothelial cells, KLF6 knockdown inhibited the expression of ATF3 but not CCL2, suggesting the regulatory role of KLF6 in ATF3 expression. Overall, this study uncovered a previously unknown role of KLF6 in TiNF-induced vascular effects both in vitro and in vivo.

Biosafety materials: Ushering in a new era of infectious disease diagnosis and treatment with the CRISPR/Cas system.

Despite multiple virus outbreaks over the past decade, including the devastating coronavirus disease 2019 (COVID-19) pandemic, the lack of accurate and timely diagnosis and treatment technologies has wreaked havoc on global biosecurity. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system has the potential to address these critical needs for tackling infectious diseases to detect viral nucleic acids and inhibit viral replication. This review summarizes how the CRISPR/Cas system is being utilized for the treatment and diagnosis of infectious diseases with the help of biosafety materials and highlights the design principle and in vivo and in vitro efficacy of advanced biosafety materials used to deal with virus attacks.

Effects of mental resilience on neuroendocrine hormones level changes induced by sleep deprivation in servicemen.

The aim of this study was to investigate the effects of mental resilience on the changes of serum rennin, angiotensin, and cortisol level induced by sleep deprivation in servicemen. By random cluster sampling, a total of 160 servicemen, aged from 18 to 30, were selected to undergo 24-hour total sleep deprivation and administered the military personnel mental resilience scale after the deprivation procedure. The sleep deprivation procedure started at 8 a.m. on Day 8 and ended at 8 a.m. on Day 9 after 7 days of normal sleep for baseline preparation. Blood samples were drawn from the 160 participants at 8 a.m. respectively on Day 8 and Day 9 for hormonal measurements. All blood samples were analyzed using radioimmunoassay. As hypothesized, serum rennin, angiotensin II, and cortisol level of the participants after sleep deprivation were significantly higher than those before (P < 0.05). The changes of serum rennin and cortisol in the lower mental resilience subgroup were significantly greater (P < 0.05); problem-solving skill and willpower were the leading influence factors for the increases of serum rennin and cortisol respectively induced by sleep deprivation. We conclude that mental resilience plays a significant role in alleviating the changes of neurohormones level induced by sleep deprivation in servicemen.