Injectable hydrogel harnessing foreskin mesenchymal stem cell-derived extracellular vesicles for treatment of chronic diabetic skin wounds.

Chronic skin wounds are a serious complication of diabetes with a high incidence rate, which can lead to disability or even death. Previous studies have shown that mesenchymal stem cells derived extracellular vesicles (EVs) have beneficial effects on wound healing. However, the human foreskin mesenchymal stem cell (FSMSCs)-derived extracellular vesicle (FM-EV) has not yet been isolated and characterized. Furthermore, the limited supply and short lifespan of EVs also hinder their practical use. In this study, we developed an injectable dual-physical cross-linking hydrogel (PSiW) with self-healing, adhesive, and antibacterial properties, using polyvinylpyrrolidone and silicotungstic acid to load FM-EV. The EVs were evenly distributed in the hydrogel and continuously released. In vivo and vitro tests demonstrated that the synergistic effect of EVs and hydrogel could significantly promote the repair of diabetic wounds by regulating macrophage polarization, promoting angiogenesis, and improving the microenvironment. Overall, the obtained EVs-loaded hydrogels developed in this work exhibited promising applicability for the repair of chronic skin wounds in diabetes patients.

VDR is a potential prognostic biomarker and positively correlated with immune infiltration: a comprehensive pan-cancer analysis with experimental verification.

The vitamin D receptor (VDR) is a transcription factor that mediates a variety of biological functions of 1,25-dihydroxyvitamin D3. Although there is growing evidence of cytological and animal studies supporting the suppressive role of VDR in cancers, the conclusion is still controversial in human cancers and no systematic pan-cancer analysis of VDR is available. We explored the relationships between VDR expression and prognosis, immune infiltration, tumor microenvironment, or gene set enrichment analysis (GSEA) in 33 types of human cancers based on multiple public databases and R software. Meanwhile, the expression and role of VDR were experimentally validated in papillary thyroid cancer (PTC). VDR expression decreased in 8 types and increased in 12 types of cancer compared with normal tissues. Increased expression of VDR was associated with either good or poor prognosis in 13 cancer types. VDR expression was positively correlated with the infiltration of cancer-associated fibroblasts, macrophages, or neutrophils in 20, 12, and 10 cancer types respectively and this correlation was experimentally validated in PTC. Increased VDR expression was associated with increased percentage of stromal or immune components in tumor microenvironment (TME) in 24 cancer types. VDR positively and negatively correlated genes were enriched in immune cell function and energy metabolism pathways, respectively, in the top 9 highly lethal tumors. Additionally, VDR expression was increased in PTC and inhibited cell proliferation and migration. In conclusion, VDR is a potential prognostic biomarker and positively correlated with immune infiltration as well as stromal or immune components in TME in multiple human cancers.

Ultrasound imaging guided targeted sonodynamic therapy enhanced by magnetophoretically controlled magnetic microbubbles.

Sonodynamic therapy (SDT) utilizes ultrasonic excitation of a sensitizer to generate reactive oxygen species (ROS) to destroy tumor. Two dimensional (2D) black phosphorus (BP) is an emerging sonosensitizer that can promote ROS production to be used in SDT but it alone lacks active targeting effect and showed low therapy efficiency. In this study, a stable dispersion of integrated micro-nanoplatform consisting of BP nanosheets loaded and Fe3O4 nanoparticles (NPs) connected microbubbles was introduced for ultrasound imaging guided and magnetic field directed precision SDT of breast cancer. The targeted ultrasound imaging at 18 MHz and efficient SDT effects at 1 MHz were demonstrated both in-vitro and in-vivo on the breast cancer. The magnetic microbubbles targeted deliver BP nanosheets to the tumor site under magnetic navigation and increased the uptake of BP nanosheets by inducing cavitation effect for increased cell membrane permeability via ultrasound targeted microbubble destruction (UTMD). The mechanism of SDT by magnetic black phosphorus microbubbles was proposed to be originated from the ROS triggered mitochondria mediated apoptosis by up-regulating the pro-apoptotic proteins while down-regulating the anti-apoptotic proteins. In conclusion, the ultrasound theranostic was realized via the magnetic black phosphorus microbubbles, which could realize targeting and catalytic sonodynamic therapy.

Mussel-inspired "plug-and-play" hydrogel glue for postoperative tumor recurrence and wound infection inhibition.

Currently, clinical tumor resection is faced with two options: open and minimally invasive surgery. Open surgery is easy to completely remove the lesion but is prone to infection, while minimally invasive surgery recovers faster but may cause tumor recurrence. To fill the shortcomings of the two surgical modes and make the choice for tumor resection more effortlessly, we developed a postoperative black phosphorus-Ag nanocomposites-loaded dopamine-modified hyaluronic acid-Pluronic® F127 (BP-Ag@HA-DA-Plu) hydrogel implantation system that can prevent tumor recurrence and wound infection simultaneously. Experiments have shown that the hydrogel system combined with 808 nm near-infrared (NIR) irradiation has excellent anti-tumor, antibacterial, and wound healing abilities. Additionally, unlike existing surgical hydrogel products that require inconvenient in-situ cross-linking, the BP-Ag@HA-DA-Plu hydrogel system offers "plug-and-play" functionality during surgery due to its thermo-responsiveness, injectability, and adhesion, thereby greatly improving the efficiency of surgery.

Robust boron nanoplatform provokes potent tumoricidal activities via inhibiting heat shock protein.

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is a promising treatment for breast cancer. However, its therapeutic efficiency is often compromised due to the heat-induced up-regulation of heat shock proteins, which confer photothermal resistance. To solve this urgent problem, PEGylated two-dimensional boron nanosheets (B-PEG)-which allow both multimodal imaging and photothermal conversion-were loaded with gambogic acid (GA), which can inhibit heat shock protein 90 (Hsp90). Experimental findings indicated that this combination of B-PEG and GA could serve as an integrated drug delivery system for cancer diagnosis and treatment. It could be used to administer mild PTT as well as chemotherapy for breast cancer, provide improved anti-tumor effects, and reduce the toxicity of PTT, all while inhibiting breast cancer growth. This drug delivery system could offer a novel tool for administering chemotherapy combined with PTT while avoiding the adverse effects of traditional PTT.

Light-induced tumor theranostics based on chemical-exfoliated borophene.

Among 2D materials (Xenes) which are at the forefront of research activities, borophene, is an exciting new entry due to its uniquely varied optical, electronic, and chemical properties in many polymorphic forms with widely varying band gaps including the lightest 2D metallic phase. In this paper, we used a simple selective chemical etching to prepare borophene with a strong near IR light-induced photothermal effect. The photothermal efficiency is similar to plasmonic Au nanoparticles, with the added benefit of borophene being degradable due to electron deficiency of boron. We introduce this selective chemical etching process to obtain ultrathin and large borophene nanosheets (thickness of ~4 nm and lateral size up to ~600 nm) from the precursor of AlB2. We also report first-time observation of a selective Acid etching behavior showing HCl etching of Al to form a residual B lattice, while HF selectively etches B to yield an Al lattice. We demonstrate that through surface modification with polydopamine (PDA), a biocompatible smart delivery nanoplatform of B@PDA can respond to a tumor environment, exhibiting an enhanced cellular uptake efficiency. We demonstrate that borophene can be more suitable for safe photothermal theranostic of thick tumor using deep penetrating near IR light compared to gold nanoparticles which are not degradable, thus posing long-term toxicity concerns. With about 40 kinds of borides, we hope that our work will open door to more discoveries of this top-down selective etching approach for generating borophene structures with rich unexplored thermal, electronic, and optical properties for many other technological applications.

Glioma diagnosis and therapy: Current challenges and nanomaterial-based solutions.

Glioma is often referred to as one of the most dreadful central nervous system (CNS)-specific tumors with rapidly-proliferating cancerous glial cells, accounting for nearly half of the brain tumors at an annual incidence rate of 30-80 per a million population. Although glioma treatment remains a significant challenge for researchers and clinicians, the rapid development of nanomedicine provides tremendous opportunities for long-term glioma therapy. However, several obstacles impede the development of novel therapeutics, such as the very tight blood-brain barrier (BBB), undesirable hypoxia, and complex tumor microenvironment (TME). Several efforts have been dedicated to exploring various nanoformulations for improving BBB permeation and precise tumor ablation to address these challenges. Initially, this article briefly introduces glioma classification and various pathogenic factors. Further, currently available therapeutic approaches are illustrated in detail, including traditional chemotherapy, radiotherapy, and surgical practices. Then, different innovative treatment strategies, such as tumor-treating fields, gene therapy, immunotherapy, and phototherapy, are emphasized. In conclusion, we summarize the article with interesting perspectives, providing suggestions for future glioma diagnosis and therapy improvement.

Mesenchymal stem cell-derived extracellular vesicles protect retina in a mouse model of retinitis pigmentosa by anti-inflammation through miR-146a-Nr4a3 axis.

BACKGROUND: Retinitis pigmentosa is a rod-cone degenerative disease that induces irreversible vision loss. This study probed the protective capacity of mesenchymal stem cell-derived small EVs (MSC-EVs) on the retinas of rd10 mice and the underlying mechanism. METHODS: MSC-EVs were injected into the vitreous of rd10 mice at postnatal day 14 and P21; morphology and function were examined at P28. The mechanism of action was explored by using co-culture of photoreceptor cell line 661 W and microglia cell line BV2. RESULTS: Treatment with MSC-EVs increased the survival of photoreceptors and preserved their structure. Visual function, as reflected by optomotor and electroretinogram responses, was significantly enhanced in MSC-EVs-treated rd10 mice. Mechanistically, staining for Iba1, GFAP, F4/80, CD68 and CD206 showed that MSC-EVs suppressed the activation of microglial, Müller glial and macrophages. Furthermore, western blotting showed that the treatment inhibited the NF-κB pathway. RNA-seq and qPCR showed that MSC-EVs upregulated anti-inflammatory cytokines while downregulating pro-inflammatory cytokines. MSC-EVs application in vitro decreased the number of TUNEL-positive 661 W cells co-cultured with LPS-stimulated BV2, with similar impact on the cytokine expression as in vivo study. Genetic screening predicted miR-146a to be the downstream target of MSC-EVs, which was detected in MSC-EVs and upregulated in co-cultured 661 W cells and BV2 cells after MSC-EVs treatment. Upregulation of miR-146a by using its mimic decreased the expression of the transcription factor Nr4a3, and its downregulation inhibition promoted Nr4a3 expression in both 661 W and BV2 cells. Nr4a3 was further identified as the target gene of miR-146a by dual-luciferase assay. Furthermore, overexpressing miR-146a significantly decreased the expression of LPS-induced pro-inflammatory cytokines in BV2 cells. CONCLUSIONS: MSC-EVs delays retinal degeneration in rd10 mice mainly by its anti-inflammatory effect via the miR-146a-Nr4a3axis. Hence, MSC-EVs may be used in the treatment of neurodegenerative diseases.

C/EBPß mediates anti-proliferative effects of 1,25(OH)2D on differentiated thyroid carcinoma cells.

Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy and highly expresses the receptor for 1,25-dihydroxyvitamin D (1,25(OH)2D). However, it is unclear whether 1,25(OH)2D regulates DTC proliferation and differentiation. Here, we found that 1,25(OH)2D3 inhibited proliferation but not differentiation of the DTC cells. Notably, CYP27B1was elevated in DTC cells and 25-hydroxyvitamin D3 (25(OH)D3) reduced DTC cell proliferation. Knockdown of VDR did not affect the anti-proliferative effects of 1,25(OH)2D3. However, knockdown of CCAAT enhancer-binding protein ß (C/EBPß)abolished 1,25(OH)2D3-suppressed DTC cell proliferation. In addition, 1,25(OH)2D3 induced phosphorylation and translocation of C/EBPßto the nucleus from the cytoplasm. However, inhibition of p38 mitogen-activated protein kinases (MAPK) abrogated 1,25(OH)2D3-induced phosphorylation and nuclear translocation of C/EBPßas well as 1,25(OH)2D3-suppressed DTC cell proliferation. Knockdown of C/EBPßreduced the expression of Notch3. Knockdown of Notch3 blocked 1,25(OH)2D3-suppressed DTC cell proliferation. In the DTC cell-derived xenograft SCID mouse, knockdown of C/EBPßmarkedly increased tumor growth and proliferation and decreased apoptosis. In DTC patients, C/EBPßwas predominantly located in the cytoplasm of DTC cells in the tumor tissue when compared with adjacent non-cancerous tissue in which C/EBPßis located in the nucleus. In conclusion, C/EBPßstimulated Notch3signaling via the p38 MAPK-dependent pathway mediates the inhibitory effect of 1,25(OH)2D on DTC cell proliferation.

Vitamin D receptor regulates proliferation and differentiation of thyroid carcinoma via the E-cadherin-ß-catenin complex.

Thyroid cancer has the fastest rising incidence among cancers, especially for differentiated thyroid carcinoma (DTC). Although the prognosis of DTC is relatively good, if it changes to anaplastic thyroid carcinoma (ATC), the prognosis will be very poor. The prognosis of DTC is largely depending on the degree of cell differentiation and proliferation. However, whether the vitamin D receptor (VDR) plays a role in regulating the proliferation and the differentiation of DTC cells is unclear. In the present study, we found that VDR was upregulated in DTC tissues compared to the adjacent non-cancerous tissue. Knockdown of VDR increased proliferation and decreased differentiation proliferation in DTC cells in vitro as well as DTC cell-derived xenografts in vivo. In contrast, overexpression of VDR had an opposite effect. Knockdown of E-cadherin abolished VDR-induced suppression of proliferation and enhancement of differentiation of the DTC cells. Knockdown of ß-catenin partially reversed the effect of the VDR knockdown. VDR increases the levels of E-cadherin in the plasma membrane and decreases the levels of ß-catenin in the nucleus. VDR binds to E-cadherin and ß-catenin in the plasma membrane of the DTC cell. Taken together, VDR inhibits DTC cell proliferation and promotes differentiation via regulation of the E-cadherin/ß-catenin complex, potentially representing novel clues for a therapeutic strategy to attenuate thyroid cancer progression.

A Regioselectively Oxidized 2D Bi/BiOx Lateral Nano-Heterostructure for Hypoxic Photodynamic Therapy.

Optoelectronic science and 2D nanomaterial technologies are currently at the forefront of multidisciplinary research and have numerous applications in electronics and photonics. The unique energy and optically induced interfacial electron transfer in these nanomaterials, enabled by their relative band alignment characteristics, can provide important therapeutic modalities for healthcare. Given that nano-heterostructures can facilitate photoinduced electron-hole separation and enhance generation of reactive oxygen species (ROS), 2D nano-heterostructure-based photosensitizers can provide a major advancement in photodynamic therapy (PDT), to overcome the current limitations in hypoxic tumor microenvironments. Herein, a bismuthene/bismuth oxide (Bi/BiOx)-based lateral nano-heterostructure synthesized using a regioselective oxidation process is introduced, which, upon irradiation at 660 nm, effectively generates 1 O2 under normoxia but produces cytotoxic •OH and H2 under hypoxia, which synergistically enhances PDT. Furthermore, this Bi/BiOx nano-heterostructure is biocompatible and biodegradable, and, with the surface molecular engineering used here, it improves tumor tissue penetration and increases cellular uptake during in vitro and in vivo experiments, yielding excellent oxygen-independent tumor ablation with 660 nm irradiation, when compared with traditional PDT agents.

2D materials for bone therapy.

Due to their prominent physicochemical properties, 2D materials are broadly applied in biomedicine. Currently, 2D materials have achieved great success in treating many diseases such as cancer and tissue engineering as well as bone therapy. Based on their different characteristics, 2D materials could function in various ways in different bone diseases. Herein, the application of 2D materials in bone tissue engineering, joint lubrication, infection of orthopedic implants, bone tumors, and osteoarthritis are firstly reviewed comprehensively together. Meanwhile, different mechanisms by which 2D materials function in each disease reviewed below are also reviewed in detail, which in turn reveals the versatile functions and application of 2D materials. At last, the outlook on how to further broaden applications of 2D materials in bone therapies based on their excellent properties is also discussed.

Overcoming barriers in photodynamic therapy harnessing nano-formulation strategies.

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.

pH-responsive black phosphorus quantum dots for tumor-targeted photodynamic therapy.

Black phosphorus quantum dots(BPQDs) have shown a good application prospect in the field of tumor therapy due to their photoelectric effect and good biodegradability. Due to the active endocytosis and fast metabolic efficiency of tumor cells, BPQDs are easy to be absorbed by tumor cells. However, this does not guarantee that BPQDs will be completely targeted to tumor cells, and normal cells will also absorb BPQDs. Because the cell membrane is negatively charged, BPQDs are also negatively charged and are not easily absorbed by cells under the action of electrostatic repulsion. Surface pegylation is the most common modification method of black phosphorus at present. However, surface pegylation can reduce the uptake of BPQDs by tumor cells. Positive PEG is also easy to be recognized and swallowed by the reticuloendothelial system. The inherent instability and poor tumor targeting of BPQDs under physiological conditions limit further research and clinical application. For this purpose, we selected cationic polymer polyethylenimine (PEI) to modify BPQDs and then added RGD peptides targeting tumor cells. An outer layer of negatively charged PEG+DMMA makes the nanosystem more stable . In the acidic environment of the tumor, the PEG layer has a charge reversal, and the positively charged PEI and the RGD polypeptide BPQDs targeted by the tumor cells are released into the tumor cells. It provides a new method for efficiently and accurately transporting BPQDs, a novel photosensitive nanomaterial, into tumor cells for photodynamic therapy.

Photodynamic immunotherapy of cancers based on nanotechnology: recent advances and future challenges.

Photodynamic therapy (PDT) is a non-invasive or minimally-invasive treatment which applies photosensitizers (PSs) to create reactive oxygen species (ROS) exposed to light trigger to destroy cancer cells. PDT can activate host anti-tumor immune responses but not powerful enough to kill metastatic tumors. Because of its carrier advantage, imaging, and therapeutic function together with enhanced permeability and retention (EPR) effect, nano-materials have already been used in photo-immunotherapy. Herein, photodynamic immunotherapy (PDIT) based on nanotechnology seems to be a hopeful new form of cancer therapy. In this article, we firstly summarize the recent development in photodynamic immunotherapy based on nanotechnology.

Prodrug-Loaded Zirconium Carbide Nanosheets as a Novel Biophotonic Nanoplatform for Effective Treatment of Cancer.

Conventional chemotherapy and photothermal therapy (PTT) face many major challenges, including systemic toxicity, low bioavailability, ineffective tissue penetration, chemotherapy/hyperthermia-induced inflammation, and tumor angiogenesis. A versatile nanomedicine offers an exciting opportunity to circumvent the abovementioned limitations for their successful translation into clinical practice. Here, a promising biophotonic nanoplatform is developed based on the zirconium carbide (ZrC) nanosheet as a deep PTT-photosensitizer and on-demand designed anticancer prodrug SN38-Nif, which is released and activated by photothermia and tumor-overexpressed esterase. In vitro and in vivo experimental evidence shows the potent anticancer effects of the integrated ZrC@prodrug biophotonic nanoplatform by specifically targeting malignant cells, chemotherapy/hyperthermia-induced tumor inflammation, and angiogenesis. In mouse models, the ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer.

Black phosphorus-based photothermal therapy with aCD47-mediated immune checkpoint blockade for enhanced cancer immunotherapy.

Here, we describe a combination strategy of black phosphorus (BP)-based photothermal therapy together with anti-CD47 antibody (aCD47)-based immunotherapy to synergistically enhance cancer treatment. Tumour resistance to immune checkpoint blockades in most cancers due to immune escape from host surveillance, along with the initiation of metastasis through immunosuppressive cells in the tumour microenvironment, remains a significant challenge for cancer immunotherapy. aCD47, an agent for CD47/SIRPα axis blockade, induces modest phagocytic activity and a low response rate for monotherapy, resulting in failures in clinical trials. We showed that BP-mediated ablation of tumours through photothermal effects could serve as an effective strategy for specific immunological stimulation, improving the inherently poor immunogenicity of tumours, which is particularly useful for enhancing cancer immunotherapy. BP in combination with aCD47 blockade activates both innate and adaptive immunities and promotes local and systemic anticancer immune responses, thus offering a synergistically enhanced effect in suppression of tumour progression and in inducing abscopal effects for inhibition of metastatic cancers. Our combination strategy provides a promising platform in which photothermal agents could help to enhance the therapeutic efficacy of immunotherapy.

Advanced nanomaterials for hypoxia tumor therapy: challenges and solutions.

In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.

Liquid-phase exfoliation of black sesame to create a nanoplatform for in vitro photoluminescence and photothermal therapy.

Aim: The present study aims to apply the facile liquid-phase exfoliation (LPE) strategy to fabricate 2D organic materials and thus to broaden the family of biocompatible and multifunctional 2D materials. Materials & methods: 2D material-organic melanin and cellulose nanosheets were synthesized from black sesame hull using LPE. Photoluminescence and photothermal properties of the nanosheets were assessed, as well as stability and cell killing ability. Results: The prepared 2D nanoplatform exhibited broad and multiple photoluminescent emission bands. It also demonstrated efficient photothermal cancer therapy with excellent biocompatibility. Conclusion: The present study could open an avenue in exfoliating organic materials using the LPE strategy. This could make the fabrication of multifunctional 2D organic materials more efficient and broaden the family of biocompatible 2D nanomaterials.