Emerging evidence indicates that osteoclasts direct osteoblastic bone formation. MicroRNAs (miRNAs) have a crucial role in regulating osteoclast and osteoblast function. However, whether miRNAs mediate osteoclast-directed osteoblastic bone formation is mostly unknown. Here, we show that increased osteoclastic miR-214-3p associates with both elevated serum exosomal miR-214-3p and reduced bone formation in elderly women with fractures and in ovariectomized (OVX) mice. Osteoclast-specific miR-214-3p knock-in mice have elevated serum exosomal miR-214-3p and reduced bone formation that is rescued by osteoclast-targeted antagomir-214-3p treatment. We further demonstrate that osteoclast-derived exosomal miR-214-3p is transferred to osteoblasts to inhibit osteoblast activity in vitro and reduce bone formation in vivo. Moreover, osteoclast-targeted miR-214-3p inhibition promotes bone formation in ageing OVX mice. Collectively, our results suggest that osteoclast-derived exosomal miR-214-3p transfers to osteoblasts to inhibit bone formation. Inhibition of miR-214-3p in osteoclasts may be a strategy for treating skeletal disorders involving a reduction in bone formation.

The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here, we show that exposure of mice to cold led to activation of angiogenesis in both white and brown adipose tissues. In the inguinal depot, cold exposure resulted in elevated expression levels of brown-fat-associated proteins, including uncoupling protein-1 (UCP1) and PGC-1alpha. Proangiogenic factors such as VEGF were upregulated, and endogenous angiogenesis inhibitors, including thrombospondin, were downregulated. In wild-type mice, the adipose tissues became hypoxic during cold exposure; in UCP1(-/-) mice, hypoxia did not occur, but, remarkably, the augmented angiogenesis was unaltered and was thus hypoxia independent. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis and significantly impaired nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage resulted in the opposite effects: increased adipose vascularity and nonshivering thermogenesis capacity. Our findings have conceptual implications concerning application of angiogenesis modulators for treatment of obesity and metabolic disorders.

Charge-reversal functional gold nanoparticles first prepared by layer-by-layer technique were employed to deliver small interfering RNA (siRNA) and plasmid DNA into cancer cells. Polyacrylamide gel electrophoresis measurements of siRNA confirmed the occurrence of the charge-reversal property of functional gold nanoparticles. The expression efficiency of enhanced green fluorescent protein (EGFP) was improved by adjuvant transfection with charge-reversal functional gold nanoparticles, which also had much lower toxicity to cell proliferation. Lamin A/ C, an important nuclear envelope protein, was effectively silenced by lamin A/C-siRNA delivered by charge-reversal functional gold nanoparticles, whose knockdown efficiency was better than that of commercial Lipofectamine 2000. Confocal laser scanning microscopic images indicated that there was more cy5-siRNA distributed throughout the cytoplasm for cyanine 5-siRNA/ polyethyleneimine/cis-aconitic anhydride-functionalized poly(allylamine)/polyethyleneimine/11-mercaptoundecanoic acid-gold nanoparticle (cy5-siRNA/PEI/PAH-Cit/PEI/MUA-AuNP) complexes. These results demonstrate the feasibility of using charge-reversal functional gold nanoparticles as a means of improving the nucleic acid delivery efficiency.Keywords gold nanoparticles; charge-reversal polyelectrolyte; drug delivery; layer-by-layer assembly; siRNA delivery Over the past decade, due to good biocompatibility, easy synthesis, monodispersity, and ready functionalization, gold nanoparticles have emerged as an attractive candidate for delivery of various payloads into cells, such as small drug molecules or large biomolecules, 1-5 such as DNA and siRNA. [6][7][8][9][10][11][12][13] The intracellular release could be triggered by glutathione (GSH), 3 pH, or external (e.g., light) stimuli. 1,4,[14][15][16][17] siRNA has emerged recently as a promising method for biological research and holds great potential for treatment of human * Address correspondence to liangxj@nanoctr.cn. ⊥ These authors contributed equally to this work. Supporting Information Available:Preparation process of charge-reversal polyelectrolyte-coated gold nanoparticles using layer-bylayer technique; TEM images of colloidal AuNPs after the coating steps; fluorescence microscope image of 293T cells transfected with DNA/PEI/PAH-Cit/PEI/MUA-AuNP complexes; and cell viability of HeLa cells treated with PEI/PAH-Cit/PEI/MUA-AuNPs and nucleic acid complexes by MTT assay. This material is available free of charge via the Internet at http://pubs.acs.org. [18][19][20] Nucleic acid was mostly loaded by gold nanoparticles through thiol linkages or electrostatic interaction with cationic gold nanoparticles. [6][7][8][9][10][11][12][13]21,22 Elbakry et al. first developed the PEI/siRNA/PEI-AuNP system to deliver siRNA into cells and knockdown the expression of target gene based on the self-assembly layer-by-layer technology. 11 PEI, which has strong escape capacity from the endosome due to its so-called "proton sponge" effect and is usually a gold standa...

Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy.amphiphilic dendrimers | supramolecular nanomicelles | drug delivery | cancer treatment | nanodrugs A lthough considerable progress has been made in cancer therapy, the complete cure and eradication of cancer remains one of the greatest challenges at present. A well-known hurdle is the drug resistance induced by chemotherapeutics, causing high recurrence rate and therapeutic failure (1). Moreover, high systemic toxicity of traditional anticancer drugs is another reason for eventual poor clinical outcome. To address these problems, the application of nanotechnology for drug delivery is widely expected to bring new hope for cancer treatment (2-6). Nanoparticle-based drug delivery systems can repress many drawbacks of traditional chemotherapeutics, such as high systematic toxicity and low therapeutic efficacy caused often by poor drug bioavailability, frequently related to the stability, solubility, and nonspecificity of drugs (2-8). In addition, nanodrugs with tailored properties can overcome drug resistance by increasing the drug accessibility and drug sensitivity via high local drug concentration achieved at tumor lesion through enhanced permeation and retention (EPR) effect (9-11). As a result, there is an increasing interest to develop effective nanodrugs for cancer treatment, and some of such systems have already made their way to clinical trials (2, 12, 13).Among various nanotechnology-based drug delivery systems, such as liposomes, nanomicelles, and nanotubes (7,8,14), nanomicelles have gained particular interest in cancer therapy by virtue of their appealing advantages such as high drug loading for effective therapeutic potency and small size (<30 nm) for deep tumor penetration (15, 16). The most common nanomicelles are constructed with lipids and amphiphilic polymers (12, 13). However, lipid-based nanomicelles have the drawback of limited stability, whereas polymers are plagued with dispersed molecular weight...