Surface Mineralization of Engineered Bacterial Outer Membrane Vesicles to Enhance Tumor Photothermal/Immunotherapy.

Gram-negative bacteria can naturally produce nanosized spherical outer membrane vesicles (OMVs) with a lipid bilayer membrane, possessing immunostimulatory capabilities to be potentially applied in tumor therapy. However, the systemic toxicity induced by pathogen-associated molecular patterns (PAMPs) of OMVs is the main obstacle for their clinical translation. Herein, melanin-loaded OMVs were produced with a genetic engineering strategy and further coated with calcium phosphate (CaP) to reduce their toxicity to enhance tumor treatment effects. Wild-type bacterium Escherichia coli Nissle 1917 (EcN) was genetically engineered to highly express tyrosinase to catalyze the intracellular synthesis of melanin, giving melanin-loaded OMVs (OMVMel). To reduce the systemic toxicity in tumor therapy, OMVMel was coated with CaP by surface mineralization to obtain OMVMel@CaP. In comparison with OMVMel, OMVMel@CaP showed lower systemic inflammatory responses in healthy mice and less damage to the liver, spleen, lung, and kidney, so the administration dose could be increased to enhance the antitumor effect. In the acidic tumor microenvironment, the CaP shell disintegrated to release OMVMel to trigger antitumor immune responses. Under costimulation of OMVMel acting as immunoadjuvants and the damage-associated molecular patterns (DAMPs) released by the photothermal effect, the efficiency of tumor photothermal/immunotherapy was largely boosted through promoting the infiltration of matured DCs, M1 macrophages, and activated CD8+ T cells, decreasing the ratio of MDSCs in tumors.

Genetically engineered probiotics for an optical imaging-guided tumor photothermal therapy/immunotherapy.

Bacteria-based cancer therapy (BCT) has been extensively investigated because of the tumor targeting and antitumor immunity activating abilities of bacteria over traditional nanodrugs, but their potential systemic toxicity poses a challenge. Therefore, it is important to visualize the precise localization and real-time distribution of bacteria in vivo to guide the treatment. Herein, biogenetically engineered Escherichia coli Nissle 1917 (EcN) were constructed to highly express tyrosinase to intracellularly generate cyanine 5-labeled melanin-like polymers (Cy5-Mel), thus endowing them with a bright fluorescence and an excellent photothermal performance upon NIR laser irradiation, thereby inducing the intense immunogenic death of tumor cells and release of tumor-associated antigens. Acting as adjuvants, bacteria can greatly stimulate the maturation of dendritic (DC) cells. The in vivo behaviors of these bacteria was monitored via noninvasive optical imaging when they were intravenously administrated to tumor-bearing mice. From this, NIR exposure on tumor sites was carried out at an appropriate time point to induce the damage to tumor cells and for the modulation of tumor immune microenvironments. Thus, via a simple bioengineering strategy, a promising bacteria-based theranostic platform was constructed for tumor treatment.

Engineered Extracellular Vesicles to Enhance Antigen Presentation for Boosting Light-Driven Tumor Immunotherapy.

Extracellular vesicles (EVs) have emerged as potential tools for tumor-target therapy accompanied with activating anticancer immune responses by serving as an integrated platform, but usually suffered from the limited cross presentation of tumor-associated antigen by dendritic cells (DCs). Here, a straightforward engineering strategy to construct heat shock proteins 70 (HSP70) highly expressed EVs incapsulated with Te nanoparticles (Te@EVsHSP70 ) for tumor photothermal therapy triggering improved immunotherapy is proposed. Tumor cells are firstly used as bioreactors for intracellular synthesis of Te nanoparticles, and NIR irradiation is subsequently introduced to upregulate the expression of HSP70 to give engineered Te@EVsHSP70 through exocytosis. Te@EVsHSP70 exhibits excellent photothermal performance and enhanced tumor antigen capture capability, which induces significant immunogenic death of tumor cells and improves DCs maturation both in vitro and in vivo. Thus, the engineered EVs demonstrate superior antitumor efficacy through photothermal effect and following provoked antitumor immune responses. This work provides a facile method to fabricate multifunctional EVs-based drug delivery system for improving photothermal-triggered tumor immunotherapy.

Bimetallic Ions Functionalized Metal-Organic-Framework Nanozyme for Tumor Microenvironment Regulating and Enhanced Photodynamic Therapy for Hypoxic Tumor.

Photodynamic therapy (PDT), as a light irradiation inducing reactive oxygen species (ROS) generation for cancer treatment, offers facile and promising solutions with respect to spatiotemporal control of ROS generation, and minimizes the systemic toxicity and side effects for highly precise tumor therapy. However, the PDT efficiency is often severely compromised by the complex tumor microenvironment (TME), such as the hypoxic condition and overexpressed antioxidants. Here, for the first time, a bimetallic ion-modified metal-organic framework nanozyme (Zr4+ -MOF-Ru3+ /Pt4+ -Ce6@HA, ZMRPC@HA) is designed. ZMRPC@HA with catalase (CAT) and glutathione oxidase (GSHOx) mimetic activities, can efficiently regulate TME by generation of O2 and deplete the GSH synergistically for enhancing the long-term PDT efficacy toward the hypoxic tumor. The in vitro cell inhibition and in vivo on tumor xenograft evaluations demonstrate the PDT strategy by using ZMRPC@HA can successfully inhibit the differentiation and proliferation of tumor cells under a 660 nm laser irradiation in deep tissues. These findings open a new avenue for the design of multimetallic ions functionalized MOF-based nanozymes with multienzyme mimetic activities toward the antitumor and various other biological applications.

The protective role of microbiota in the prevention of MPTP/P-induced Parkinson's disease by resveratrol.

Parkinson's disease (PD) is a tricky neurodegenerative disease characterized with motor deficits and gastrointestinal (GI) dysfunction. Gut microbiota disturbance is reported to be involved in the clinical phenotypes of PD and its pathogenesis through the brain-gut-microbiota axis. Resveratrol is a natural polyphenol that possesses various biological activities in alleviating many diseases, including PD. The present study was aimed to investigate the role of gut microbiota in resveratrol-treated PD mice. A chronic mouse model of PD was generated via the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid (MPTP/P) for 5 consecutive weeks. Resveratrol was orally administered once a day (30 mg kg-1 d-1) for a total of 8 weeks. From the 6th week to the 8th week, fecal microbiota transplantation (FMT) was performed from resveratrol-treated PD mice to PD mice to evaluate the contribution of resveratrol-shaped microbiota in the alleviation of PD. The results showed that FMT from resveratrol-shaped microbiota remarkably alleviated the mice phenotype from PD progression, including increased latency in the rotarod, shortened beam walking time, increased the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and enriched TH-positive fiber density in the striatum. Further experiments revealed that FMT could ameliorate the GI dysfunction by increasing the small intestinal transport rate and the colon length, decreasing the relative abundances of inflammatory cytokines (TNF-α, IL-6 and IL-1ß) in colon epithelial tissue. The 16S rDNA sequencing indicated that FMT attenuated the gut microbial dysbiosis in PD mice by increasing the abundances of Prevotellaceae, Rikenellaceae, Erysipelotrichaceae, Blautia and Alistipes, lowering the ratio of Fimicutes/Bacteroidetes, and decreasing the abundances of Lachnospiraceae and Akkermansia. Therefore, results in this study demonstrated that gut microbiota played a vital role in the prevention of PD progression, and the shaping of the gut microbiota was the pharmacological mechanism of resveratrol in alleviating the phenotype of Parkinson's disease in PD mice.

The role of imaging in targeted delivery of nanomedicine for cancer therapy.

Nanomedicines overcome the pharmacokinetic limitations of traditional drug formulations and have promising prospect in cancer treatment. However, nanomedicine delivery in vivo is still facing challenges from the complex physiological environment. For the purpose of effective tumor therapy, they should be designed to guarantee the five features principle, including long blood circulation, efficient tumor accumulation, deep matrix penetration, enhanced cell internalization and accurate drug release. To ensure the excellent performance of the designed nanomedicine, it would be better to monitor the drug delivery process as well as the therapeutic effects by real-time imaging. In this review, we summarize strategies in developing nanomedicines for efficiently meeting the five features of drug delivery, and the role of several imaging modalities (fluorescent imaging (FL), magnetic resonance imaging (MRI), computed tomography (CT), photoacoustic imaging (PAI), positron emission tomography (PET), and electron microscopy) in tracing drug delivery and therapeutic effect in vivo based on five features principle.

Bacterially Synthesized Tellurium Nanorods for Elimination of Advanced Malignant Tumor by Photothermal Immunotherapy.

Probiotic Escherichia coli Nissle 1917 (EcN) are employed as a bioreactor for intracellularly synthesizing tellurium nanorods (TeNRs) providing a biohybrid therapeutic platform (Te@EcN) for the elimination of advanced malignant tumor by photothermal immunotherapy. Te@EcN is found to possess superior photothermal property upon near-infrared irradiation, and can efficiently accumulate and retain in tumors, although EcN loses proliferation ability after the synthesis of TeNRs, thus inducing considerable immunogenic tumor cell death. Under co-stimulation by EcN acting as immunoadjuvants, maturation of dendritic cells and priming of cytotoxic T cells are largely promoted. In addition, Te@EcN can reprogram tumor-associated macrophages to ameliorate the immunosuppressive tumor microenvironment. Thus, tumor metastasis and recurrence can be efficiently suppressed. Most importantly, owing to the non-pathogenicity of probiotic EcN and their non-proliferative characteristics after TeNRs synthesis, Te@EcN is found to be rapidly metabolized and cleared from the normal tissues, showing very slight acute side effects in healthy mice even at a relatively high administration dose. Therefore, the proposed combined therapeutic strategy based on bacteria-synthesized TeNRs may find great potential in improving bacteria-mediated tumor therapy with increased antitumor efficacy and reduced toxicity.

Albumin-Templated Bi2Se3-MnO2 Nanocomposites with Promoted Catalase-Like Activity for Enhanced Radiotherapy of Cancer.

Novel and effective radiosensitizers that can enhance radiosensitivity of tumor tissues and increase the local radiation dose are highly desirable. In this work, templated by bovine serum albumin (BSA), Bi2Se3-MnO2 nanocomposites (Bi2Se3-MnO2@BSA) were fabricated via biomineralization, while Bi2Se3 nanodots act as radiosensitizers to increase the local radiation dosage because of their strong X-ray attenuation ability, and MnO2 with catalase-like activity can increase the oxygen concentration in tumors by triggering the decomposition of tumor endogenous H2O2 so as to improve the hypoxia-associated radioresistance of tumors. Owing to the interaction of the two components in the interface, Bi2Se3-MnO2@BSA showed promoted catalytic activity compared to MnO2@BSA, favoring tumor radiotherapy (RT) sensitization. BSA templating enabled the nanocomposites with high colloidal stability and biocompatibility as well as satisfactory tumor targeting both in vitro and in vivo; thus, an enhanced RT efficacy was obtained. Moreover, the proposed Bi2Se3-MnO2@BSA exhibited excellent performances in computerized tomography and magnetic resonance imaging. Thus, this work provides a tumor microenvironment-responsive multifunctional theranostic nanoagent with an improved performance for imaging-guided tumor RT sensitization.

Chitooligosaccharides Prevents the Development of Colitis-Associated Colorectal Cancer by Modulating the Intestinal Microbiota and Mycobiota.

Gut microbes play a crucial role in the development of colorectal cancer. Chitooligosaccharides (COS), are oligomer that are depolymerized from chitosan and possess a wide range of biological activities. In this study, the effects of COS on colorectal cancer (CRC) development were evaluated using azoxymethane and dextran sulfate sodium (AOM/DSS) induced mouse model of CRC (CACM). In the COS-treated CRC group (CMCOS), COS protected mice from CRC by decreasing the disease activity index, tumor incidences and multiplicity, and the mRNA levels of COX-2, IL-6, TNF-α, IL-1ß, IL-10, and IKK-ß mRNA in colonic epithelial cells. The results of a cage-exchanged experiment, in which mice from the CACMe and CMCOSe treatments exchanged cages every day to interact with microbes, showed that gut microbes play an important role in preventing CAC by COS. The abundances of fecal bacteria (total bacteria, Lactobacillus, Enterococcus, Fusobacterium nucleatum and butyrate-producing bacteria) were detected by qPCR on the 0th, 1st, 3rd, 6th, 9th, and 10th weekends. Furthermore, microbiota and mycobiota were analyzed by high-throughput sequencing on an Illumina MiSeq PE300 system. COS protected mice from CRC by reversing the imbalance of bacteria and fungi, especially by reducing the abundance of Escherichia-Shigella, Enterococcus, and Turicibacter, and increasing the levels of Akkermansia, butyrate-producing bacteria and Cladosporium.