Ultrasound-triggered functional hydrogel promotes multistage bone regeneration.

The dysfunction of bone mesenchymal stem cells (BMSCs), caused by the physical and chemical properties of the inflammatory and repair phases of bone regeneration, contributes to the failure of bone regeneration. To meet the spatiotemporal needs of BMSCs in different phases, designing biocompatible materials that respond to external stimuli, improve migration in the inflammatory phase, reduce apoptosis in the proliferative phase, and clear the hurdle in the differentiation phase of BMSCs is an effective strategy for multistage repair of bone defects. In this study, we designed a cascade-response functional composite hydrogel (Gel@Eb/HA) to regulate BMSCs dysfunction in vitro and in vivo. Gel@Eb/HA improved the migration of BMSCs by upregulating the expression of chemokine (C-C motif) ligand 5 (CCL5) during the inflammatory phase. Ultrasound (US) triggered the rapid release of Ebselen (Eb), eliminating the accumulation of reactive oxygen species (ROS) in BMSCs, and reversing apoptosis under oxidative stress. Continued US treatment accelerated the degradation of the materials, thereby providing Ca2+ for the osteogenic differentiation of BMSCs. Altogether, our study highlights the prospects of US-controlled intelligent system, that provides a novel strategy for addressing the complexities of multistage bone repair.

Dipsacus Asperoides-Derived Exosomes-Like Nanoparticles Inhibit the Progression of Osteosarcoma via Activating P38/JNK Signaling Pathway.

Introduction: Osteosarcoma is a prevalent and highly malignant primary bone tumor. However, current clinical therapeutic drugs for osteosarcoma are not suitable for long-term use due to significant side effects. Therefore, there is an urgent need to develop new drugs with fewer side effects. Dipsacus asperoides C. Y. Cheng et T. M. Ai, a traditional Chinese medicine, is commonly used for its anti-inflammatory, anti-pain, bone fracture healing, and anti-tumor effects. In this study, we investigated the effects of exosome-like nanoparticles derived from Dipsacus asperoides (DAELNs) on osteosarcoma cells in vitro and in vivo. Methods: DAELNs were isolated and purified from Dipsacus asperoides and their physical and chemical properties were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The cellular uptake of DAELNs in osteosarcoma cells was analyzed by PKH26 staining. The proliferation, invasion, migration, and apoptosis of osteosarcoma cells were assessed using CCK8 assay, EdU assay, colony-formation assay, transwell assay, wound healing assay, and mitochondrial membrane potential measurement, respectively. The regulatory mechanism of DAELNs inhibiting the progression of osteosarcoma via activating P38/JNK signaling pathway was investigated using Western blotting and immunohistochemistry. Moreover, the therapeutic effects of DAELNs were evaluated using in vivo small animal imaging assay, HE staining, and immunohistochemistry. Results: Our results showed that DAELNs inhibited the proliferation, invasion, migration, and fostered the apoptosis of osteosarcoma cells in vitro and suppressed the tumor growth of osteosarcoma cells in a xenograft nude mouse model. Furthermore, the bio-distribution of DiD-labeled DAELNs showed preferential targeting of osteosarcoma tumors and excellent biosafety in histological analysis of the liver and kidney. Mechanistically, DAELNs activated the P38/JNK signaling pathway-induced apoptosis. Conclusion: Taken together, DAELNs are novel, natural, and osteosarcoma-targeted agents that can serve as safe and effective therapeutic approaches for the treatment of osteosarcoma.

Precise Engineering of a Se/Te Nanochaperone for Reinvigorating Cancer Radio-Immunotherapy.

Facilely synthesized nanoradiosensitizers with well-controlled structure and multifunctionality are greatly desired to address the challenges of cancer radiotherapy. In this work, a universal method is developed for synthesizing chalcogen-based TeSe nano-heterojunctions (NHJs) with rod-, spindle-, or dumbbell-like morphologies by engineering the surfactant and added selenite. Interestingly, dumbbell-shaped TeSe NHJs (TeSe NDs) as chaperone exhibit better radio-sensitizing activities than the other two nanostructural shapes. Meanwhile, TeSe NDs can serve as cytotoxic chemodrugs that degrade to highly toxic metabolites in acidic environment and deplete GSH within tumor to facilitate radiotherapy. More importantly, the combination of TeSe NDs with radiotherapy significantly decreases regulatory T cells and M2-phenotype tumor-associated macrophage infiltrations within tumors to reshape the immunosuppressive microenvironment and induce robust T lymphocytes-mediated antitumor immunity, resulting in great abscopal effects on combating distant tumor progression. This study provides a universal method for preparing NHJ with well-controlled structure and developing nanoradiosensitizers to overcome the clinical challenges of cancer radiotherapy.

Designing Lactate Dehydrogenase-Mimicking SnSe Nanosheets To Reprogram Tumor-Associated Macrophages for Potentiation of Photothermal Immunotherapy.

Rapid glycolysis of tumor cells produces excessive lactate to trigger acidification of the tumor microenvironment (TME), leading to the formation of immunosuppressive TME and tumor-associated macrophage (TAM) dysfunction. Therefore, reprogramming TAMs by depleting lactate with nanodrugs is expected to serve as an effective means of tumor-targeted immunotherapy. Herein, we report the use of lactic acid dehydrogenase (LDH)-mimicking SnSe nanosheets (SnSe NSs) loaded with a carbonic anhydrase IX (CAIX) inhibitor to reconstruct an acidic and immunosuppressive TME. As expected, this nanosystem could reprogram the TAM to achieve M1 macrophage activation and could also restore the potent tumor-killing activity of macrophages while switching their metabolic mode from mitochondrial oxidative phosphorylation to glycolysis. In addition, the repolarizing effect of SnSe NSs on macrophages was validated in a coculture model of bone marrow-derived macrophages, in three patient-derived malignant pleural effusion and in vivo mouse model. This study proposes a feasible therapeutic strategy for depleting lactate and thus ameliorating acidic TME employing Se-containing nanosheets, which could further amply the effects of TAM-based antitumor immunotherapy.

Designing intelligent nano-bomb with on-demand site-specific drug burst release to synergize with high-intensity focused ultrasound cancer ablation.

High intensity focused ultrasound (HIFU) has been widely used in clinical treatment of cervical cancer for its non-invasiveness and sharp treatment margins with very low complication rates. However, how to intensify the therapeutic efficacy of HIFU by specifically focusing the ultrasound energy on targeting pathological tissues is still a bottleneck for it to realize successful cancer ablation. Herein, a multifunctional organic-inorganic hybrid nanovesicles, by coating ultrathin silica shell on the surface of poly (lactic-co-glycolic acid) (PLGA) loaded with perfluorocarbon (PFOB), hydrophobic antitumor ruthenium complex (RuPOP) and superparamagnetic Fe3O4, has been designed to achieve synchronous ultrasound (US)/magnetic resonance imaging (MR) dual mode imaging-guided HIFU-triggered chemotherapy. The introduction of PFOB in this nanosystem could cause phase transition and make it gasification to cause collapse of the outer ultrathin silicon shell under HIFU irradiation, which results in enhanced intensive mechanical stress during blasting and enhanced therapeutic effect. The blasting behavior of this nanosystem triggered by HIFU also induced the on-demand RuPOP burst release in tumor site, thus maximizing the inhibition on residual tumor induced by inhomogeneous HIFU ablation. Taken together, this treatment strategy could overcome the inevitable tumor recurrence and significantly reduces systemic side effects of HIFU, thus could be further developed for noninvasive cancer therapy.

Correction: A highly selective dual-therapeutic nanosystem for simultaneous anticancer and antiangiogenesis therapy.

Correction for 'A highly selective dual-therapeutic nanosystem for simultaneous anticancer and antiangiogenesis therapy' by Lizhen He et al., J. Mater. Chem. B, 2017, 5, 8228-8237, DOI: 10.1039/C7TB02163A.

Designing immunogenic nanotherapeutics for photothermal-triggered immunotherapy involving reprogramming immunosuppression and activating systemic antitumor responses.

Low tumor mutational burden and absence of T cells within the tumor sites are typical characteristics of "cold immune tumors" that paralyzes the immune system. The strategy of reversing "cold tumors" to "hot tumors" infiltrated high degree of T cells in order to activate anti-tumor immunity has attracted lots of attentions. Herein, immunogenic core-shell Au@Se NPs is fabricated by gold-selenium coordination bond to realize nanoparticles-mediated local photothermal-triggered immunotherapy. As expected, incorporation of gold nanostars (AuNSs) with improved photothermal stability and conversion efficiency promotes the disintegration and transformation of selenium nanoparticles (SeNPs), thus leading to enhanced cancer cells apoptosis by producing higher hyperthermia. Moreover, the results of in vivo experiments demonstrate that the synergy between SeNPs-mediated chemotherapy and AuNSs-induced photothermal therapy not only generated a localized antitumor-immune response with excellent cancer killing effect under the presence of tumor-associated antigens, but also effectively reprogrammed the tumor associated macrophages (TAMs) from M2 to M1 phenotype with tumoricidal activity to devour distant tumors. Without a doubt, this study not only provides a potent strategy to reverse the immunosuppressive tumor microenvironment, but also offers a new insight for potential clinical application in tumor immunotherapy.

Dual-targeting nanotherapeutics antagonize hyperinsulinemia-promoted tumor growth via activating cell autophagy.

Hyperinsulinemia, a concomitant symptom in type 2 diabetes mellitus (T2DM) promotes the migration, invasion and proliferation of tumors by inhibiting autophagy. Therefore, it is necessary to search for antitumor drugs that can effectively antagonize hyperinsulinemia by promoting autophagy. In this study, dual-targeting modified selenium nanoparticles (u/A-SeNPs) were proposed as a biocompatible tumor chemotherapeutic drug to antagonize high insulin. The modification of chitosan (CS) and grafting targeted peptides (uPA/ACPP) allowed SeNPs to exert better selectivity and higher antitumor activity. The nanotherapeutics entered tumor cells through receptor-mediated endocytosis and produced excessive ROS. Meanwhile, u/A-SeNPs significantly increased the level of autophagy in tumor cells, as detected by monodansylcadaverine (MDC) and mRFP-GFP-LC3. U/A-SeNPs cause mitochondrial fragmentation to induce the cell apoptosis via the synergistic action of overproduced ROS and activated autophagy. In conclusion, this study proposes a feasible method for the synthesis of dual-targeting nanomedicines, and it also provides a new strategy for the application of Se-based nanotherapeutics in tumor therapy under hyperinsulinemia conditions.

Construction of Urokinase-Type Plasminogen Activator Receptor-Targeted Heterostructures for Efficient Photothermal Chemotherapy against Cervical Cancer To Achieve Simultaneous Anticancer and Antiangiogenesis.

Rational design and construction of theranostic nanomedicines based on clinical characteristics of cervical cancer is an important strategy to achieve precise cancer therapy. Herein, we fabricate a cervical cancer-targeting gold nanorod-mesoporous silica heterostructure for codelivery of synergistic cisplatin and antiangiogenic drug Avastin (cisplatin-AuNRs@SiO2-Avastin@PEI/AE105) to achieve synergistic chemophotothermal therapy. Based on database analysis and clinical sample staining, conjugation of the AE105-targeting peptide obviously improves the intracellular uptake of the nanosystem and enhances the cancer-killing ability and selectivity between cervical cancer and normal cells. It could also be used to specifically monitor the urokinase-type plasminogen activator receptor (uPAR) expression level in clinical cervical specimens, which would be an early indicator of prognosis in cancer treatment. Under 808 nm laser irradiation, the nanosystem demonstrates smart NIR-light-triggered drug release and prominent photodynamic activity via induction of reactive oxygen species overproduction-mediated cell apoptosis. The nanosystem also simultaneously suppresses HeLa tumor growth and angiogenesis in vivo, with no evident histological damage observed in the major organs. In short, this study not only provides a clinical data-based rational design strategy of smart nanomedicine for precise treatment and rapid clinical diagnosis of cervical cancer but also contributes to the development of the clinical translation of nanomedicines.

Designing Core-Shell Gold and Selenium Nanocomposites for Cancer Radiochemotherapy.

Radiotherapy is an important regime for treating malignant tumors. There is interest in the development of radiosensitizers to increase the local treatment efficacy under a relatively low and safe radiation dose. In this study, we designed Au@Se-R/A nanocomposites (Au@Se-R/A NCs) as nano-radiosensitizer to realize synergistic radiochemotherapy based on the radiotherapy sensitization property of Au nanorods (NRs) and antitumor activity of Se NPs. In vitro studies show that the combined treatment of A375 melanoma cells in culture with NCs and X-ray induces cell apoptosis through alteration in expression of p53 and DNA-damaging genes and triggers intracellular ROS overproduction, leading to greatly enhanced anticancer efficacy. Further studies using clinically used radiotherapy equipment demonstrate that the combined treatment of NCs and X-ray significantly inhibits the tumor growth in vivo and shows negligible acute toxicity to the major organs. Taken together, this study provides a strategy for clinical translation application of nanomedicne in cancer radiochemotherapy.

A highly selective dual-therapeutic nanosystem for simultaneous anticancer and antiangiogenesis therapy.

The rational design of highly selective and cancer-targeted nanodrug delivery systems with attractive anticancer activities is urgently needed for future exploration and translational application of nanomedicine. As angiogenesis and tumor growth could be mutually enhanced, dual therapeutic nanomedicine with simultaneous antiangiogenesis and anticancer activities is practical for cancer therapy. Therefore, herein we have rationally designed functionalized mesoporous silica nanoparticles (MSNs) to realize the dual therapy of tumor growth and angiogenesis based on the biochemical similarity of membranes of cancer cells and angiogenic cells. This nanosystem demonstrates high selectivity in vivo against cancer cells with high integrin expression levels in two-tumor bearing models, and could simultaneously inhibit cancer cell growth and disrupt tumor neovasculature, thus achieving satisfactory in vivo anticancer efficacy. Interestingly, the nanosystem triggers ROS overproduction in both cancer and human umbilical vein endothelial cells, which activates various downstream signaling pathways to regulate cell cycle arrest and apoptosis. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs to normal tissues and prolongs blood circulation in vivo. Therefore, this study provides a simple approach for facile manufacture of a potent nanodrug delivery system that could achieve dual therapy of tumor growth and angiogenesis.

Functionalized halloysite nanotube by chitosan grafting for drug delivery of curcumin to achieve enhanced anticancer efficacy.

Halloysite nanotubes (HNTs) have a unique tubular structure in nanoscale, and have shown potential as novel carriers for various drugs. Coating the nanotubes with a hydrophilic polymer shell can significantly decrease the toxicity and provide colloidal stability during blood circulation. Here, we synthesized chitosan grafted HNTs (HNTs-g-CS) and investigated their potential as a nano-formulation for the anticancer drug curcumin. The structure and properties of HNTs-g-CS were characterized using water contact angle, zeta-potential, Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and transmission electron microscopy (TEM) techniques. HNTs-g-CS exhibit a maximum 90.8% entrapment efficiency and 3.4% loading capacity of curcumin, which are higher than those of raw HNTs. HNTs-g-CS also show no obvious hemolytic phenomenon and good stability in serum. The cumulative release ratio of curcumin from HNTs-g-CS/curcumin at cell lysate after 48 hours is 84.2%. The curcumin loaded HNTs-g-CS show specific toxicity to various cancer cell lines, including HepG2, MCF-7, SV-HUC-1, EJ, Caski and HeLa, and demonstrate an inhibition concentration of IC50 at 5.3-192 µM as assessed by cytotoxicity studies. The anticancer activity of this nanoformulation is extremely high in EJ cells compared with the other cancer cell lines. The cell uptake of HNTs-g-CS is confirmed by fluorescence microscopy. Flow cytometric analysis of curcumin loaded HNTs-g-CS shows that curcumin loaded HNTs-g-CS increase apoptosis on EJ cells. The content of ROS created by HNTs-g-CS/curcumin is more than that of free curcumin. All these results suggest that HNTs-g-CS are potential nanovehicles for anticancer drug delivery in cancer therapy.