Biological barriers are essential physiological protective systems and obstacles to drug delivery. Nanoparticles (NPs) can access the paracellular route of biological barriers, either causing adverse health impacts on humans or producing therapeutic opportunities. This Review introduces the structural and functional influences of NPs on the key components that govern the paracellular route, mainly tight junctions, adherens junctions, and cytoskeletons. Furthermore, we evaluate their interaction mechanisms and address the influencing factors that determine the ability of NPs to open the paracellular route, which provides a better knowledge of how NPs can open the paracellular route in a safer and more controllable way. Finally, we summarize limitations in the research models and methodologies of the existing research in the field and provide future research direction. This Review demonstrates the in-depth causes for the reversible opening or destruction of the integrity of barriers generated by NPs; more importantly, it contributes insights into the design of NP-based medications to boost paracellular drug delivery efficiency.

A novel bioactive inorganic material containing silicon, calcium and oxygen, calcium silicate (Ca 2 SiO 4 , C 2 S) with a CaO-SiO 2 ingredient, has been identified as a potential candidate for artificial bone. Autophagy has an essential function in adult tissue homoeostasis and tumorigenesis. However, little is known about whether silicate nanoparticles (C 2 S NPs) promote osteoblastic differentiation by inducing autophagy. Here we investigated the effects of C 2 S NPs on bone marrow mesenchymal stem cell differentiation (BMSCs) in osteoblasts. Furthermore, we identified the osteogenic gene and protein expression in BMSCs treated with C 2 S NPs. We found that autophagy is important for the ability of C 2 S NPs to induce osteoblastic differentiation of BMSCs. Our results showed that treatment with C 2 S NPs upregulated the expression of BMP2, UNX2, and OSX in BMSCs, and significantly promoted the expression of LC3 and Beclin, while P62 (an autophagy substrate) was downregulated. C 2 S NP treatment could also enhance Alizarin red S dye (ARS), although alkaline phosphatase (ALP) activity was not significantly changed. However, all these effects could be partially reversed by 3-MA. We then detected potential signaling pathways involved in this biological effect and found that C 2 S NPs could activate autophagy by suppressing mTOR and facilitating ULK1 expression. Autophagy further activated β-catenin expression and promoted osteogenic differentiation. In conclusion, C 2 S NPs promote bone formation and osteogenic differentiation in BMSCs by activating autophagy. They achieve this effect by activating mTOR/ ULK1, inducing autophagy, and subsequently triggering the WNT/β-catenin pathway to boost the differentiation and biomineralization of osteoblasts.

Photosensitizers play a critical role in photodynamic therapy (PDT). Multifunctional organic nanoparticles (NPs) that possess bright fluorescence in aggregates, high singlet oxygen (1O2) quantum yield, near-infrared (NIR) absorption and emission, large Stokes shift, two-photon bioimaging, specific organelle targeting, high PDT efficiency, as well as good biocompatibility and photostability are ideal candidate photosensitizers for image-guided PDT. Due to its enhanced fluorescence and high 1O2 generation efficiency in aggregate states, photosensitizers with aggregation-induced emission (AIE) characteristics have attracted increasing interest in PDT. In this study, a new AIE-active Schiff base 5-(((5-(7-(4-(diphenylamino)­phenyl)­benzo­[c]­[1,2,5]­thiadiazol-4-yl)­thiophen-2-yl)­methylene)­amino)-3-methylthiophene-2,4-dicarbonitrile (TBTDC) based on a D–A−π–A skeleton has been designed and synthesized, and it can be readily encapsulated by Pluronic F-127 to form uniform nanoparticles. TBTDC NPs exhibit bright NIR emission at 825 nm with a Stokes shift up to 300 nm, impressive two-photon bioimaging capability with tissue penetration deep into 300 μm, high 1O2 generation quantum yield (0.552), specific targeting to lysosome, as well as good biocompatibility and photostability. Furthermore, TBTDC NPs present remarkable cytotoxicity for tumor cells and suppression of tumor growth in nude mice through reactive oxygen species generation upon white light irradiation. These results reveal that TBTDC NPs have great potential to become excellent candidates for multifunctional organic photosensitizers for two-photon bioimaging and image-guided PDT and are promising in future clinical applications.

Cartilage defects in temporomandibular disorders (TMD) lead to chronic pain and seldom heal. Synovium-derived mesenchymal stem cells (SMSCs) exhibit superior chondrogenesis and have become promising seed cells for cartilage tissue engineering. However, local inflammatory conditions that affect the repair of articular cartilage by SMSCs present a challenge, and the specific mechanism through which the function remains unclear. Thus, it is important to explore the chondrogenesis of SMSCs under inflammatory conditions of TMD such that they can be used more effectively in clinical treatment. In this study, we obtained SMSCs from TMD patients with severe cartilage injuries. In response to stimulation with IL-1β, which is well known as one of the most prevalent cytokines in TMD, MMP13 expression increased, while that of SOX9, aggrecan, and collagen II decreased during chondrogenic differentiation. At the same time, IL-1β upregulated the expression of mTOR and decreased the ratio of LC3-II/LC3-I and the formation of autophagosomes. Further study revealed that rapamycin pretreatment promoted the migration of SMSCs and the expression of chondrogenesis-related markers in the presence of IL-1β by inducing autophagy. 3-Benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2(3H)-one (3BDO), a new activator of mTOR, inhibited autophagy and increased the expression of p-GSK3βser9 and β-catenin, simulating the effect of IL-1β stimulation. Furthermore, rapamycin reduced the expression of mTOR, whereas the promotion of LC3-II/LC3-I was blocked by the GSK3β inhibitor TWS119. Taken together, these results indicate that rapamycin enhances the chondrogenesis of SMSCs by inducing autophagy, and GSK3β may be an important regulator in the process of rapamycin-induced autophagy. Thus, inducing autophagy may be a useful approach in the chondrogenic differentiation of SMSCs in the inflammatory microenvironment and may represent a novel TMD treatment.

With the broad use of nanotechnology, the number and variety of nanoparticles that humans can be exposed to has further increased. Consequently, there is growing concern about the potential effect of maternal exposure to various nanoparticles during pregnancy on a fetus. However, the nature of this risk is not fully known. Areas covered: In this review, materno-fetal transfer of nanoparticles through the placenta is described. Both prenatal and postnatal adverse effects, such as fetal resorption, malformation and injury to various organs in mice exposed to nanoparticles are reviewed. The potential mechanisms of toxicity are also discussed. Expert opinion: The toxicology and safe application of recently developed nanoparticles has attracted much attention in the past few years. Although many studies have demonstrated the toxicology of nanoparticles in various species, only a small number of studies have examined the effect on a fetus after maternal exposure to nanoparticles. This is particularly important, because the developing fetus is especially vulnerable to the toxic effects of nanoparticles during fetal development due to the unique physical stage of the fetus. Nanoparticles may directly or indirectly impair fetal development and growth after maternal exposure to nanoparticles.

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Retinoic acid (RA) has been widely used in cosmetics and medicine. However, high concentrations of RA could cause negative effects, and carcinogenic substances can be generated by light degradation. Herein, a convenient and environmental method was developed to realize the sustained release of RA by TiO2 nanocapsules. The surface morphologies, crystalline properties, and chemical structures were characterized by SEM, XRD, FT-IR, NMR. Moreover, the effects of solubilizer, core material content, shell-forming agent, biological properties, and other factors on the nanocapsules were investigated. The results indicated that low crystallinity of anatase TiO2 shell contributed to sustained release of inner RA. The sustained-release properties were studied through the elution process. It confirmed that the RA was encapsulated in the TiO2 shell with loose structures. Light irradiation experiments proved that inner RA was well protected and released continuously. The RA-TiO2 nanocapsules showed good dispersion, sustained-release properties, long-acting antibacterial property, and photostability.

Background N6-methyladenosine (m6A) is the most prevalent epigenetic modification in eukaryotic messenger RNAs and plays a critical role in cell fate transition. However, it remains to be elucidated how m6A marks functionally impact the transcriptional cascades that orchestrate stem cell differentiation. The present study focuses on the biological function and mechanism of m6A methylation in dental pulp stem cell (DPSC) differentiation. Methods m6A RNA immunoprecipitation sequencing was utilized to assess the m6A-mRNA landscape during DPSC differentiation. Ectopic transplantation of DPSCs in immunodeficient mice was conducted to verify the in vitro findings. RNA sequencing and m6A RNA immunoprecipitation sequencing were combined to identify the candidate targets. RNA immunoprecipitation and RNA/protein stability of Noggin (NOG) were evaluated. The alteration in poly(A) tail was measured by 3′-RACE and poly(A) tail length assays. Results We characterized a dynamic m6A-mRNA landscape during DPSC mineralization with increasing enrichment in the 3′ untranslated region (UTR). Methyltransferase-like 3 (METTL3) was identified as the key m6A player, and METTL3 knockdown disrupted functional DPSC differentiation. Moreover, METTL3 overexpression enhanced DPSC mineralization. Increasing m6A deposition in the 3′ UTR restricted NOG expression, which is required for DPSC mineralization. This stage-specific m6A methylation and destabilization of NOG was suppressed by METTL3 knockdown only in differentiated DPSCs. Furthermore, METTL3 promotes the degradation of m6A-tagged NOG by shortening the poly(A) tail length in the differentiated stage. Conclusions Our results address an essential role of dynamic m6A signaling in the temporal control of DPSC differentiation and provide new insight into epitranscriptomic mechanisms in stem cell-based therapy.