In situ photothermal nano-vaccine based on tumor cell membrane-coated black phosphorus-Au for photo-immunotherapy of metastatic breast tumors.

Cancer vaccines which can activate antitumor immune response have great potential for metastatic tumors treatment. However, clinical translation of cancer vaccines remained challenging due to weak tumor antigen immunogenicity, inefficient in vivo delivery, and immunosuppressive tumor microenvironment. Nanomaterials-based photothermal treatment (PTT) triggers immunogenic cell death while providing in situ tumor-associated antigens for subsequent anti-tumor immunity. Here, an in situ photothermal nano-vaccine (designated as BCNCCM) based on cancer cell membrane (CCM) was explored by co-encapsulating immune adjuvant CpG oligodeoxynucleotide (ODN) loaded black phosphorus-Au (BP-Au) nanosheets together with an indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919) by CCM, for the elimination of primary and metastatic breast tumors. The nano-vaccine could be delivered to tumor site selectively by CCM targeting and exhibit vaccine-like functions through the combined effect of in situ generated tumor-associate agents after PTT and immune adjuvant CpG, resulting in trigger of tumor-specific immunity. Furthermore, tumor inhibition was enhanced owing to the reversed immunosuppressive microenvironment mediated by IDO inhibitors. The nano-vaccine not only had good therapeutic effect on primary and metastatic tumors, but also could prevent tumor recurrence by producing systemic immune memory. Therefore, the photothermal nano-vaccine which coordinate in situ vaccine-like function and immune modulation may be a promising stragegy for photo-immunotherapy of metastatic tumors.

Strontium-substituted sub-micron bioactive glasses inhibit ostoclastogenesis through suppression of RANKL-induced signaling pathway.

Strontium-substituted bioactive glass (Sr-BG) has shown superior performance in bone regeneration. Sr-BG-induced osteogenesis has been extensively studied; however, Sr-BG-mediated osteoclastogenesis and the underlying molecular mechanism remain unclear. It is recognized that the balance of osteogenesis and osteoclastogenesis is closely related to bone repair, and the receptor activators of nuclear factor kappaB ligand (RANKL) signaling pathway plays a key role of in the regulation of osteoclastogenesis. Herein, we studied the potential impact and underling mechanism of strontium-substituted sub-micron bioactive glass (Sr-SBG) on RANKL-induced osteoclast activation and differentiation in vitro. As expected, Sr-SBG inhibited RANKL-mediated osteoclastogenesis significantly with the experimental performance of decreased mature osteoclasts formation and downregulation of osteoclastogenesis-related gene expression. Furthermore, it was found that Sr-SBG might suppress osteoclastogenesis by the combined effect of strontium and silicon released through inhibition of RANKL-induced activation of p38 and NF-κB pathway. These results elaborated the effect of Sr-SBG-based materials on osteoclastogenesis through RANKL-induced downstream pathway and might represent a significant guidance for designing better bone repair materials.

Synergistic effect of strontium and silicon in strontium-substituted sub-micron bioactive glass for enhanced osteogenesis.

Strontium-substituted sub-micron bioactive glasses (Sr-SBG) have been reported to have enhanced osteogenic differentiation capacity compared to sub-micron bioactive glasses (SBG) in our previous study. However, the underlying molecular mechanisms of such beneficial effect of Sr-SBG are still not fully understood. In this study, we synthesized Sr-SBG, studied the effects of Sr-SBG on proliferation and osteogenic differentiation of mouse mesenchymal stem cells (mMSCs), and identified the molecular mechanisms of the enhancement effect of Sr-SBG on mMSCs. The results demonstrated that Sr-SBG had more profound promotion effect on proliferation and osteogenic differentiation of mMSCs than SBG and SrCl2 group which containing identical Sr concentration with Sr-SBG group. RT-qPCR and western blot analysis showed that the mRNA expressions and protein expressions involved in NFATc and Wnt/ß-catenin signaling pathways were all upregulated mediated by Sr-SBG, while only Wnt/ß-catenin signaling pathway related genes upregulated in SBG group and only NFATc signaling pathway activated in SrCl2 group, suggesting that NFATc and Wnt/ß-catenin signaling pathways played important roles in osteogenesis enhancement induced by Sr-SBG. To conform the above conclusion, cyclosporin A (CSA) was applied to inhibit NFATc signaling pathway. It was found that the enhanced osteogenic differentiation of mMSCs induced by Sr-SBG was partially abrogated and the activated Wnt/ß-catenin signaling pathway was also inhibited in part. However, the effects of SBG on proliferation and osteogenesis of mMSCs were unimpaired, yet the effects of SrCl2 were greatly suppressed. Taken together, these results indicated that strontium activated NFATc signaling pathway and silicate activated Wnt/ß-catenin signaling pathway might synergistically mediated the enhanced osteogenesis induced by Sr-SBG.

Strontium-Substituted Submicrometer Bioactive Glasses Modulate Macrophage Responses for Improved Bone Regeneration.

Host immune response induced by foreign bone biomaterials plays an important role in determining their fate after implantation. Hence, it is well worth designing advanced bone substitute materials with beneficial immunomodulatory properties to modulate the host-material interactions. Bioactive glasses (BG), with excellent osteoconductivity and osteoinductivity, are regarded as important biomaterials in the field of bone regeneration. In order to explore a novel BG-based osteoimmunomodulatory implant with the capacity of potentially enhancing bone regeneration, it is a possible way to regulate the local immune microenvironment through manipulating macrophage polarization. In this study, strontium-substituted submicrometer bioactive glass (Sr-SBG) was prepared as an osteoimmunomodulatory bone repair material. To investigate whether the incorporation of Sr into SBG could synergistically improve osteogenesis by altering macrophage response, we systematically evaluated the interaction between Sr-SBG and macrophage during the process of bone regeneration by in vitro biological evaluation and in vivo histological assessment. It was found that the Sr-SBG modulates proper inflammatory status, leading to enhanced osteogenesis of mouse mesenchymal stem cells (mMSCs) and suppressed osteoclastogenesis of RAW 264.7 cells compared to SBG without strontium substitution. In vivo study confirmed that Sr-SBG initiated a less severe immune response and had an improved effect on bone regeneration than SBG, which corresponded with the in vitro evaluation. In conclusion, these findings suggested that Sr-SBG could be a promising immunomodulatory bone repair material designed for improved bone regeneration.

Optical clearing of porcine skin tissue in vitro studied by Raman microspectroscopy.

In present work, we studied the effect of optical clearing on porcine skin in vitro with glycerol by Raman microspectroscopy, denoted as RM, at various time intervals of 0, 15, 30, 45, 60, and 75 min respectively. The results showed that the addition of glycerol significantly improved the depth of RM measurement, and enhanced the recovery of skin tissue Raman spectra that were not overlapped with the glycerol Raman spectra over time. Moreover, it was found that the Raman signals resembled the native spectrum of the molecules in porcine skin with a negligible frequency shift. Furthermore, we evaluated the extent of optical clearing in porcine skin by utilizing various concentrations of 40%, 60%, and 80% glycerol solution. The results demonstrated that with the increase of concentration of glycerol, the optical clearing of porcine skin was much improved.

Synergistic effect of chemo-photothermal therapy using PEGylated graphene oxide.

Graphene has shown great potential both in photothermal therapy and drug delivery. Herein, we developed doxorubicin-loaded PEGylated nanographene oxide (NGO-PEG-DOX) to facilitate combined chemotherapy and photothermal therapy in one system. In this work, we studied the ablation of tumor both in vivo and in vitro by the combination of photothermal therapy and chemotherapy using this functional graphene oxide. The ability of the NGO-PEG-DOX nanoparticle to combine the local specific chemotherapy with external near-infrared (NIR) photothermal therapy significantly improved the therapeutic efficacy of cancer treatment. Compared with chemotherapy or photothermal therapy alone, the combined treatment demonstrated a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, lower systematic toxicity of NGO-PEG-DOX than DOX was proved by the pathologic examination of main organs in our toxicity study.