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.

Innovation-driven trend shaping COVID-19 vaccine development in China.

Confronted with the Coronavirus disease 2019 (COVID-19) pandemic, China has become an asset in tackling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and mutation, with several innovative platforms, which provides various technical means in this persisting combat. Derived from collaborated researches, vaccines based on the spike protein of SARS-CoV-2 or inactivated whole virus are a cornerstone of the public health response to COVID-19. Herein, we outline representative vaccines in multiple routes, while the merits and plights of the existing vaccine strategies are also summarized. Likewise, new technologies may provide more potent or broader immunity and will contribute to fight against hypermutated SARS-CoV-2 variants. All in all, with the ultimate aim of delivering robust and durable protection that is resilient to emerging infectious disease, alongside the traditional routes, the discovery of innovative approach to developing effective vaccines based on virus properties remains our top priority.

Biodegradable electrospun nanofibrous platform integrating antiplatelet therapy-chemotherapy for preventing postoperative tumor recurrence and metastasis.

The perioperative trauma-related platelet recruitment and activation severely affect tumor recurrence and metastasis. Therefore, efficiently killing residual tumor cells and simultaneously inhibiting platelet activation to block platelet-cancer cell interaction might be a promising strategy to prevent postoperative tumor recurrence and metastasis. Methods: Biodegradable PLGA electrospun nanofibrous films co-delivering doxorubicin-loaded tumor repopulating cell-derived microparticles (DOX-MPs) and aspirin (ASA) were developed as the implant materials (DOX-MPs/ASA@NF) for postoperative in-situ treatment. The characterization, cytotoxicity against tumor cells, inhibition in platelet activation-triggered proliferation, migration and metastasis of tumor cells and in vivo anti-recurrence and anti-metastasis activity induced by DOX-MPs/ASA@NF were systematically evaluated. Results: PLGA nanofibrous films facilitate the enhanced distribution of DOX-MPs as well as DOX-MPs and ASA release in a time-programmed manner within the tumor resection cavity. The released DOX-MPs efficiently kill the residual tumor cells, while ASA decreases platelet activation and inhibits platelet-promoted proliferation, migration and metastasis of tumor cells, resulting in the remarkable inhibition of postoperative tumor recurrence and metastasis. Conclusions: DOX-MPs/ASA@NF may be a promising candidate to prevent the recurrence and metastasis of resectable tumors.

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.

Ultrasound responsive erythrocyte membrane-derived hybrid nanovesicles with controlled drug release for tumor therapy.

An ultrasound responsive erythrocyte membrane-derived hybrid nanovesicle drug delivery system (DOX/HMME@FA-NL) is constructed by the membrane fusion functionalization strategy for controlled drug release and enhanced tumor therapy. The reliability and effectiveness of the membrane fusion strategy are confirmed through characterization of the particle size and zeta potential, Förster energy resonance transfer and fluorescence co-localization analyses. The DOX/HMME@FA-NL could be triggered for reactive oxygen species (ROS) generation under ultrasound stimulation. And the unsaturated phospholipids in DOX/HMME@FA-NL can be oxidized by ROS, leading to the destruction of the structure of the hybrid membrane to achieve the controlled release of drugs, thereby enhancing their tumor cell killing effect. Besides, the linkage of the folate targeting group also enhances the tumor targeting ability of DOX/HMME@FA-NL. H22 tumor-bearing mice were intravenously injected with DOX/HMME@FA-NL and treated with ultrasound, they achieved better than expected tumor sonodynamic response treatment effects.

Precise Cancer Anti-acid Therapy Monitoring Using pH-Sensitive MnO2@BSA Nanoparticles by Magnetic Resonance Imaging.

Microfluctuations in a pH gradient create a harsh microenvironment in tumors, leaving behind the most aggressive, invasive, and drug-resistant tumor cells. Directly visualizing the spatiotemporal distribution of pH variations and accurately quantifying the dynamic acid-base changes during cancer treatment are critical to estimate prognosis and to evaluate therapeutic efficacy. However, the quantification of subtle pH variations dynamically and noninvasively remains challenging. The purpose of this study is to determine and visualize dynamic acid-base changes in solid tumors during anti-acid treatments by magnetic resonance imaging (MRI) using pH-sensitive nanoparticles. We report the development of pH-sensitive nanoparticles, MnO2@BSA, that rapidly and strongly amplify the MR contrast signal in response to the extracellular acidic environment of solid tumors. The spatiotemporal distribution and dynamic fluctuations of pH heterogeneity in NCI-H460 lung tumors were observed with MnO2@BSA at different time points after an anti-acid treatment with esomeprazole, which directly interferes with the acidic microenvironment of the tumor. Imaging results were validated using a pH microsensor. MRI of pH-sensitive MnO2@BSA nanoparticles provided direct readouts of the kinetics of pH gradient fluctuations during esomeprazole treatment. A significant MR signal reduction was observed at the 48 h time point after treatment. The manipulated extracellular pH changes detected noninvasively by MRI coincided with the extracellular pH fluctuations measured with a pH microsensor (pH 6.12-6.63). Immunofluorescence and Western blot analyses confirmed the expression of V-ATPase in NCI-H460 lung cancer cells, which could be inhibited by esomeprazole, as detected by ELISA assay. Overall, these results demonstrate that MnO2@BSA MRI has great potential as a noninvasive tool to accurately monitor pH fluctuations, thereby paving the way for the dynamic detection of acidic microenvironments in vivo without the need for pH microsensors.

Tumor-targeting inorganic nanomaterials synthesized by living cells.

Inorganic nanomaterials (NMs) have shown potential application in tumor-targeting theranostics, owing to their unique physicochemical properties. Some living cells in nature can absorb surrounding ions in the environment and then convert them into nanomaterials after a series of intracellular/extracellular biochemical reactions. Inspired by that, a variety of living cells have been used as biofactories to produce metallic/metallic alloy NMs, metalloid NMs, oxide NMs and chalcogenide NMs, which are usually automatically capped with biomolecules originating from the living cells, benefitting their tumor-targeting applications. In this review, we summarize the biosynthesis of inorganic nanomaterials in different types of living cells including bacteria, fungi, plant cells and animal cells, accompanied by their application in tumor-targeting theranostics. The mechanisms involving inorganic-ion bioreduction and detoxification as well as biomineralization are emphasized. Based on the mechanisms, we describe the size and morphology control of the products via the modulation of precursor ion concentration, pH, temperature, and incubation time, as well as cell metabolism by a genetic engineering strategy. The strengths and weaknesses of these biosynthetic processes are compared in terms of the controllability, scalability and cooperativity during applications. Future research in this area will add to the diversity of available inorganic nanomaterials as well as their quality and biosafety.

Engineered Cell-Derived Microparticles Bi2Se3/DOX@MPs for Imaging Guided Synergistic Photothermal/Low-Dose Chemotherapy of Cancer.

Cell-derived microparticles, which are recognized as nanosized phospholipid bilayer membrane vesicles, have exhibited great potential to serve as drug delivery systems in cancer therapy. However, for the purpose of comprehensive therapy, microparticles decorated with multiple therapeutic components are needed, but effective engineering strategies are limited and still remain enormous challenges. Herein, Bi2Se3 nanodots and doxorubicin hydrochloride (DOX) co-embedded tumor cell-derived microparticles (Bi2Se3/DOX@MPs) are successfully constructed through ultraviolet light irradiation-induced budding of parent cells which are preloaded with Bi2Se3 nanodots and DOX via electroporation. The multifunctional microparticles are obtained with high controllability and drug-loading capacity without unfavorable membrane surface destruction, maintaining their excellent intrinsic biological behaviors. Through membrane fusion cellular internalization, Bi2Se3/DOX@MPs show enhanced cellular internalization and deepened tumor penetration, resulting in extreme cell damage in vitro without considering endosomal escape. Because of their distinguished photothermal performance and tumor homing target capability, Bi2Se3/DOX@MPs exhibit admirable dual-modal imaging capacity and outstanding tumor suppression effect. Under 808 nm laser irradiation, intravenous injection of Bi2Se3/DOX@MPs into H22 tumor-bearing mice results in remarkably synergistic antitumor efficacy by combining photothermal therapy with low-dose chemotherapy in vivo. Furthermore, the negligible hemolytic activity, considerable metabolizability, and low systemic toxicity of Bi2Se3/DOX@MPs imply their distinguished biocompatibility and great potential for tumor theranostics.

NaCeF4:Gd,Tb Scintillator as an X-ray Responsive Photosensitizer for Multimodal Imaging-Guided Synchronous Radio/Radiodynamic Therapy.

Photosensitizers (PSs) that are directly responsive to X-ray for radiodynamic therapy (RDT) with desirable imaging abilities have great potential applications in cancer therapy. Herein, the cerium (Ce)-doped NaCeF4:Gd,Tb scintillating nanoparticle (ScNP or scintillator) is first reported. Due to the sensitization effect of the Ce ions, Tb ions can emit fluorescence under X-ray irradiation to trigger X-ray excited fluorescence (XEF). Moreover, Ce and Tb ions can absorb the energy of secondary electrons generated by X-ray to produce reactive oxide species (ROS) for RDT. With the intrinsic absorption of X-ray by lanthanide elements, the NaCeF4:Gd,Tb ScNPs also act as a computed tomography (CT) imaging contrast agent and radiosensitizers for radiotherapy (RT) sensitization synchronously. Most importantly, the transverse relaxation time of Gd3+ ions is shortened due to the doping of Ce and Tb ions, leading to the excellent performance of our ScNPs in T2-weighted MR imaging for the first time. Both in vitro and in vivo studies verify that our synthesized ScNPs have good performance in XEF, CT, and T2-weighted MR imaging, and a synchronous RT/RDT is achieved with significant suppression on tumor progression under X-ray irradiation. Importantly, no systemic toxicity is observed after intravenous injection of ScNPs. Our work highlights that ScNPs have potential in multimodal imaging-guided RT/RDT of deep tumors.