Solar-driven sugar production directly from CO2 via a customizable electrocatalytic-biocatalytic flow system.

Conventional food production is restricted by energy conversion efficiency of natural photosynthesis and demand for natural resources. Solar-driven artificial food synthesis from CO2 provides an intriguing approach to overcome the limitations of natural photosynthesis while promoting carbon-neutral economy, however, it remains very challenging. Here, we report the design of a hybrid electrocatalytic-biocatalytic flow system, coupling photovoltaics-powered electrocatalysis (CO2 to formate) with five-enzyme cascade platform (formate to sugar) engineered via genetic mutation and bioinformatics, which achieves conversion of CO2 to C6 sugar (L-sorbose) with a solar-to-food energy conversion efficiency of 3.5%, outperforming natural photosynthesis by over three-fold. This flow system can in principle be programmed by coupling with diverse enzymes toward production of multifarious food from CO2. This work opens a promising avenue for artificial food synthesis from CO2 under confined environments.

Imaging and monitoring of granzyme B in the immune response.

Significant progress has been made in tumor immunotherapy that uses the human immune response to kill and remove tumor cells. However, overreactive immune response could lead to various autoimmune diseases and acute rejection. Accurate and specific monitoring of immune responses in these processes could help select appropriate therapies and regimens for the patient and could reduce the risk of side effects. Granzyme B (GzmB) is an ideal biomarker for immune response, and its peptide substrate could be coupled with fluorescent dyes or contrast agents for the synthesis of imaging probes activated by GzmB. These small molecules and nanoprobes based on PET, bioluminescence imaging, or fluorescence imaging have proved to be highly GzmB specific and accuracy. This review summarizes the design of different GzmB-responsive imaging probes and their applications in monitoring of tumor immunotherapy and overreactive immune response. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Nanocodelivery of an NIR photothermal agent and an acid-responsive TLR7 agonist prodrug to enhance cancer photothermal immunotherapy and the abscopal effect.

The immunosuppressive tumor microenvironment (TME) greatly limits the actual outcome of immunotherapy. Therefore, it is urgent to develop appropriate strategies to reshape the TME and ultimately induce a strong immune response. Here, we developed a dual-functional liposome loaded with the photothermal agent IR808 near the infrared region (NIR) and Toll-like-receptor-7 (TLR7) agonist loxoribine prodrug (Lipo@IR808@Loxo) to achieve NIR light-triggered photothermal therapy (PTT) and the targeted delivery of immune adjuvants. Under NIR irradiation, Lipo@IR808@Loxo could greatly improve the efficiency of PTT to directly kill tumor cells and release tumor-associated antigens, which could work together with loaded loxoribine to relieve the immunosuppressive TME, effectively promoting the activation of antigen-presenting cells and subsequent antigen presentation. In this way, Lipo@IR808@Loxo could act as an in situ therapeutic cancer vaccine, eventually inducing a potent antitumor T-cell response. When further combined with immune checkpoint blockade, Lipo@IR808@Loxo-mediated photothermal immunotherapy could not only eliminate the primary tumors but also inhibit the growth of distant tumors, thus enhancing the abscopal effect.

Stimuli-Responsive Nanoadjuvant Rejuvenates Robust Immune Responses to Sensitize Cancer Immunotherapy.

Despite their immense therapeutic potential, cancer immunotherapies such as immune checkpoint blockers (ICBs) benefit only a small subset of patients. Toll-like receptor agonists reverse the immunosuppressive tumor microenvironment (TME) to enhance antitumor immunity, but their systemic administration induces side effects. This work describes a TME-responsive nanotherapeutic platform for the site-specific release of drug candidates in tumors with a significant antitumor efficacy. Imidazoquinoline (IMQ)-derived liposomal nanovesicles (LN-IMQ) triggered the antitumor ability of macrophages, mobilized T-cell immunity, and promoted the secretion of antitumor cytokines, explaining the synergistic effect of LN-IMQ with ICBs. LN-IMQ monotherapy observed complete tumor regression in 6/8 of 4T1-bearing mouse, and cured mice resisted secondary tumor challenge. Besides, LN-IMQ decreased the occurrence of lung metastases, being effective against advanced metastases. On the other hand, neoantigen-based cancer vaccine has very low immune responses. Here, we also verified that LN-IMQ can serve as an ideal tumor antigen delivery vector. Cancer cells in vitro treated with chemotherapeutic drugs included multiple neoantigens and high levels of damage-associated molecular patterns, which were then successfully encapsulated in LN-IMQ to obtain a "personalized nanovaccine" with artificially amplified antigenicity and adjuvant properties. This study developed an attractive potential personalized nanovaccine for chemotherapeutic-drug-induced tumor neoantigens and immunotherapy.

Artificial photosynthetic cells with biotic-abiotic hybrid energy modules for customized CO2 conversion.

Programmable artificial photosynthetic cell is the ultimate goal for mimicking natural photosynthesis, offering tunable product selectivity via reductase selection toward device integration. However, this concept is limited by the capacity of regenerating the multiple cofactors that hold the key to various reductases. Here, we report the design of artificial photosynthetic cells using biotic-abiotic thylakoid-CdTe as hybrid energy modules. The rational integration of thylakoid with CdTe quantum dots substantially enhances the regeneration of bioactive NADPH, NADH and ATP cofactors without external supplements by promoting proton-coupled electron transfer. Particularly, this approach turns thylakoid highly active for NADH regeneration, providing a more versatile platform for programming artificial photosynthetic cells. Such artificial photosynthetic cells can be programmed by coupling with diverse reductases, such as formate dehydrogenase and remodeled nitrogenase for highly selective production of formate or methane, respectively. This work opens an avenue for customizing artificial photosynthetic cells toward multifarious demands for CO2 conversion.

Chemotherapy-Induced Neoantigen Nanovaccines Enhance Checkpoint Blockade Cancer Immunotherapy.

Chemotherapeutics have the potential to increase the efficacy of cancer immunotherapies by stimulating the production of damage-associated molecular patterns (DAMPs) and eliciting mutations that result in the production of neoantigens, thereby increasing the immunogenicity of cancerous lesions. However, the dose-limiting toxicity and limited immunogenicity of chemotherapeutics are not sufficient to induce a robust antitumor response. We hypothesized that cancer cells in vitro treated with ultrahigh doses of various chemotherapeutics artificially increased the abundance, variety, and specificity of DAMPs and neoantigens, thereby improving chemoimmunotherapy. The in vitro chemotherapy-induced (IVCI) nanovaccines manufactured from cell lysates comprised multiple neoantigens and DAMPs, thereby exhibiting comprehensive antigenicity and adjuvanticity. Our IVCI nanovaccines exhibited enhanced immune responses in CT26 tumor-bearing mice, with a significant increase in CD4+/CD8+ T cells in tumors in combination with immune checkpoint inhibitors. The concept of IVCI nanovaccines provides an idea for manufacturing and artificial enhancement of immunogenicity vaccines to improve chemoimmunotherapy.

Platinum-Based Twin Drug Modulates Tumor-Infiltrating Immune Cells to Improve Immune Checkpoint Blockade Therapy.

Chemoimmunotherapy is an area of active research and development with a growing body of evidence supporting its potential benefits for the treatment of cancer. However, chemotherapy components of chemoimmunotherapy have several limitations, including systemic toxicity and poor performance in reversing the immunosuppressive tumor microenvironment. Here, we designed a twin drug, MROP, complexed with all-trans retinoic acid and oxaliplatin, and showed that the twin drug significantly enhanced the synergetic therapeutic efficacy with anti-PD-1 in a colorectal cancer mouse model. We demonstrated by mechanistic analyses of tumor tissue that the combination of anti-PD-1 and MROP induced immunogenic cell death and regulated tumor-infiltrating immune cells, including the polarization of tumor-associated macrophages toward type 1, a reduction in myeloid-derived suppressor cells, and a significant increase in the proportion of T cells, particularly CD8+ T cells. This paper provides a promising strategy for cancer treatment and new insight into the mechanism of chemoimmunotherapy.

Monophosphoryl lipid A-assembled nanovaccines enhance tumor immunotherapy.

Therapeutic cancer nanovaccines can induce strong antitumor immunity and establish long-term immune memory and have shown potential for curing tumors in some clinical trials. However, weak immunogenicity and safety concerns of nanocarriers limit the clinical translation of some therapeutic nanovaccines. Here, we developed minimal-component cancer nanovaccines, monophosphoryl lipid A (MPLA)-assembled nanovaccines (MANs), that could facilitate the clinical application of nanovaccines. The MANs were formed by protein antigens extracted from chemotherapy-induced tumor cell cultures and the amphiphilic immune adjuvant MPLA. Compared with free chemotherapy-induced antigens, MANs can activate the Toll-like receptor 4 (TLR4)-mediated signalling pathway and promote adaptive immunity against tumor antigens. Mechanistic analysis indicated that MANs induced antigen capture of DCs and promoted the activation of DCs and T cells, thereby optimizing the ratio of CD8+ T/Tregs in tumors and facilitating the transformation of the tumor immune microenvironment (TIME) from "cold" to "hot". In a CT26 colorectal cancer model, MANs+αPD-1 significantly improved the efficacy of αPD-1 treatment. Our work offers a strategy for designing minimal-component cancer nanovaccines with potential clinical benefits. STATEMENT OF SIGNIFICANCE: To address the weak immunogenicity of cancer vaccines and the safety concerns of nanocarriers, we prepared MPLA-assembled nanovaccines (MANs) using chemotherapy induced antigens and the immune adjuvant MPLA to promote cancer vaccines to clinical practice. MANs effectively internalized tumor antigens and induced DC maturation, indicating that the initial anti-tumor response had been activated. MANs+αPD-1 induced APCs, CD8+ T cells and memory T cells with positive anti-tumor effects to migrate to tumor tissue, thus leading to the transformation of the tumor immune microenvironment from "cold" to "hot". At the animal level, the combination of MANs and αPD-1 exerted synergistic effects and significantly enhanced tumor immunotherapy. Therefore, the treatment regimen of MANs+αPD-1 has potential clinical benefits.

Platinum Twin and Triplet Drugs Improve Chemoimmunotherapy.

Several chemoimmunotherapy regimens have been approved by the U.S. FDA, verifying the great clinical value and potential of the strategy. However, the immunomodulatory function of chemotherapy was insufficient, which did not provide extra overall survival benefits, especially in a head-to-head comparison of chemoimmunotherapy versus immunotherapy. Here, we engineered twin and triplet drugs derived from an immunogenic chemotherapeutic drug (oxaliplatin) and small-molecule inhibitors of negative immunoregulation pathways (COX2 and IDO) in tumors as an improved chemotherapeutic component within chemoimmunotherapy. The twin and triplet drugs exhibited significantly improved synergy with anti-PD-1 in a CT26 colorectal mouse tumor model. Mechanistic analyses revealed that the drug induced immunogenic cell death and restored tumor immune microenvironment toward tumor clearance in vivo, resulting in a great decrease in tumor-infiltrating Tregs and an increase in the CD8+ T/Treg ratio when combined with anti-PD-1. Our work expands the application of platinum twin drugs in combination with an immune checkpoint blockade.

Chemotherapy-induced nanovaccines implement immunogenicity equivalence for improving cancer chemoimmunotherapy.

Several chemoimmunotherapies have been approved by the FDA for the treatment of various cancers. Chemotherapy has the potential to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of tumor cells, promoting the release of tumor associated antigens (TAAs), tumor specific antigens (TSAs) and damage associated molecular patterns (DAMPs), and disrupting immunosuppressive microenvironments by tumor debulking. Unfortunately, systemic administration of chemotherapeutics carries side effects of blunting anti-cancer immune response through systemic immunosuppression, which deserves to be explored as an inner contradiction in chemoimmunotherapy. Here, we proposed the hypothesis of "immunogenicity equivalence" in chemoimmunotherapy that chemotherapeutics-induced immunogenic antigens and DAMPs in vitro that can subsequently be incorporated into nanovaccines, which will possess comparable immunostimulatory potential when compared to tumors treated with systemic chemotherapy in vivo. The proteomic analysis confirmed that our nanovaccines contained TAAs, TSAs and DAMPs. Improvement in treatment outcomes in tumor-bearing mice receiving anti-PD-1 and chemotherapy-induced nanovaccines was then observed. Furthermore, we demonstrated the feasibility of replacing long-term chemotherapy with nanovaccines in chemoimmunotherapy. Our nanovaccine strategy would be a general choice for formulating cancer vaccines in personalized medicine.

Utilizing chemotherapy-induced tumor RNA nanoparticles to improve cancer chemoimmunotherapy.

Chemotherapy has become a popular combination strategy to improve the response rate of immunotherapy since certain chemotherapeutic drugs kill tumor cells by an immunogenic cell death (ICD) pathway, which activates antitumor immune responses. Unfortunately, the synergistic effect of chemoimmunotherapy can be impaired due to the toxicities of chemotherapeutic agent-induced lymphatic depletion and immunosuppression. In this study, we present an approach to improve immunotherapy by using tumor RNA nanoparticles (RNA-NPs) where RNA is directly extracted from chemotherapy-treated cancer cells and then condensed by protamine via electrostatic interactions to form complexes. Such RNA-NPs can be effectively taken up by dendritic cells (DCs) in the draining lymph nodes after subcutaneous injection. Compared with noninduced tumor RNA nanoparticles (N-RNA-NPs), chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) can significantly promote DC maturation and stimulate a stronger immune response against established CT-26 colon carcinoma. Besides, C-RNA-NPs can improve the efficacy of immune checkpoint blockade (ICB) therapy by facilitating the infiltration of intratumoral T cells and increasing the ratio of CD8+ T cells to regulatory T cells (Tregs). More importantly, the synergistic effect of chemoimmunotherapy is also enhanced by treatment with C-RNA-NPs. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade therapy has been demonstrated to be effective in some advanced cancers, the low response rate has significantly limited its clinical application. To address this issue, a new strategy for improving cancer immunotherapy using chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) is developed in this work. The proposed C-RNA-NPs could be captured by dendritic cells, which were then stimulated to the maturation status to initiate an anticancer immune response. Furthermore, the response rate to immunotherapy was significantly increased by promoting intratumoral T-cell infiltration and elevating the intratumoral ratio of CD8+ T cells to regulatory T cells after treatment with C-RNA-NPs. Therefore, C-RNA-NPs have the potential to improve cancer immunotherapy.

Red blood cell-based vaccines for ameliorating cancer chemoimmunotherapy.

Immune checkpoint blockade (ICB) therapy has shown promising antitumor effects, but its immune response rate remains unsatisfactory. In recent years, chemotherapy has been proven to have synergistic effects with ICB therapy because some chemotherapeutic agents can enhance the immunogenicity of tumor cells by inducing immunogenic cell death (ICD). However, it cannot be ignored that chemotherapy often shows limited therapeutic efficacy due to high cytotoxicity, drug resistance, and some other side effects. Herein, we report a strategy to improve cancer immunotherapy by utilizing red blood cell-based vaccines (RBC-vaccines) where chemotherapy-induced tumor antigens (cAgs) are anchored onto red blood cells (RBCs) via the EDC/NHS-mediated amine coupling reaction. In this work, RBC-vaccines administered subcutaneously are primarily devoured by dendritic cells (DCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment by increasing the infiltration of intratumoral CD8+ and CD4+ T cells and elevating the intratumoral ratio of CD8+ T cells to regulatory T cells in the CT-26 colon cancer model. Finally, based on the rejection of tumor rechallenge in cured mice, the combination therapy of RBC-vaccines and αPD-1 can induce the expansion of memory T cells and thereby establish a long-term antitumor immune response. Taken together, the proposed RBC-vaccines have great potential to improve chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Immunotherapy, especially immune checkpoint blockade therapy, has made great contributions to the treatment of some advanced cancers. Unfortunately, the great majority of patients with cancer do not benefit from immunotherapy. To enhance the response rate of immunotherapy, we developed red blood cell-based vaccines (RBC-vaccines) against cancers where antigens were harvested from chemotherapy-treated cancer cells and then attached to erythrocytes via covalent surface modification. Such RBC-vaccines could provide a wide variety of tumor antigens and damage-associated molecular patterns without the use of any extra ingredients to trigger a stronger antitumor immune response. More importantly, the combination of RBC-vaccines with PD-1 blockade could significantly improve the efficacy of cancer immunotherapy and induce durable antitumor immunity.

Advances of functional nanomaterials for magnetic resonance imaging and biomedical engineering applications.

Functional nanomaterials have been widely used in biomedical fields due to their good biocompatibility, excellent physicochemical properties, easy surface modification, and easy regulation of size and morphology. Functional nanomaterials for magnetic resonance imaging (MRI) can target specific sites in vivo and more easily detect disease-related specific biomarkers at the molecular and cellular levels than traditional contrast agents, achieving a broad application prospect in MRI. This review focuses on the basic principles of MRI, the classification, synthesis and surface modification methods of contrast agents, and their clinical applications to provide guidance for designing novel contrast agents and optimizing the contrast effect. Furthermore, the latest biomedical advances of functional nanomaterials in medical diagnosis and disease detection, disease treatment, the combination of diagnosis and treatment (theranostics), multi-model imaging and nanozyme are also summarized and discussed. Finally, the bright application prospects of functional nanomaterials in biomedicine are emphasized and the urgent need to achieve significant breakthroughs in the industrial transformation and the clinical translation is proposed. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Advances in Nanotechnology Development to Overcome Current Roadblocks in CAR-T Therapy for Solid Tumors.

Chimeric antigen receptor T cell (CAR-T) therapy for the treatment of hematologic tumors has achieved remarkable success, with five CAR-T therapies approved by the United States Food and Drug Administration. However, the efficacy of CAR-T therapy against solid tumors is not satisfactory. There are three existing hurdles in CAR-T cells for solid tumors. First, the lack of a universal CAR to recognize antigens at the site of solid tumors and the compact tumor structure make it difficult for CAR-T cells to locate in solid tumors. Second, soluble inhibitors and suppressive immune cells in the tumor microenvironment can inhibit or even inactivate T cells. Third, low survival and proliferation rates of CAR-T cells in vivo significantly influence the therapeutic effect. As an emerging method, nanotechnology has a great potential to enhance cell proliferation, activate T cells, and restarting the immune response. In this review, we discuss how nanotechnology can modify CAR-T cells through variable methods to improve the therapeutic effect of solid tumors.

Advances of Nanomedicine in Radiotherapy.

Radiotherapy (RT) remains one of the current main treatment strategies for many types of cancer. However, how to improve RT efficiency while reducing its side effects is still a large challenge to be overcome. Advancements in nanomedicine have provided many effective approaches for radiosensitization. Metal nanoparticles (NPs) such as platinum-based or hafnium-based NPs are proved to be ideal radiosensitizers because of their unique physicochemical properties and high X-ray absorption efficiency. With nanoparticles, such as liposomes, bovine serum albumin, and polymers, the radiosensitizing drugs can be promoted to reach the tumor sites, thereby enhancing anti-tumor responses. Nowadays, the combination of some NPs and RT have been applied to clinical treatment for many types of cancer, including breast cancer. Here, as well as reviewing recent studies on radiotherapy combined with inorganic, organic, and biomimetic nanomaterials for oncology, we analyzed the underlying mechanisms of NPs radiosensitization, which may contribute to exploring new directions for the clinical translation of nanoparticle-based radiosensitizers.

Co-delivery of etoposide and cisplatin in dual-drug loaded nanoparticles synergistically improves chemoradiotherapy in non-small cell lung cancer models.

Chemoradiotherapy with cisplatin and etoposide is a curative management regimen for both small and non-small cell lung cancers. While the treatment regimen is effective, it also has a high toxicity profile. One potential strategy to improve the therapeutic ratio of chemoradiation is to utilize nanotherapeutics. Nanoparticle formulation of cisplatin and etoposide, however, is challenging due to the significant mismatch in chemical properties of cisplatin and etoposide. Herein we report the formulation of a polymeric nanoparticle formulation of cisplatin and etoposide using a prodrug approach. We synthesized a hydrophobic platinum prodrug, which was then co-delivered with etoposide using a nanoparticle. Using mouse models of lung cancer, we demonstrated that dual-drug loaded nanoparticles are significantly more effective than small molecule chemotherapy in chemoradiotherapy. These results support further investigation of nanoparticle-based drug formulations of combination chemotherapies and the use of nanotherapeutics in chemoradiotherapy. STATEMENT OF SIGNIFICANCE: The treatment of lung cancer often involves a combination of chemotherapy and radiation. While it can be effective, it also has a high toxicity profile. Preferential delivery of chemotherapeutics to the tumor while avoiding normal tissue would improve efficacy and lower toxicity. While this is challenging with conventional drug delivery technologies, nanotechnology offers a unique opportunity. In this study, we have engineered nanoparticles that are loaded with combination chemotherapeutics and showed such nanotherapeutics are more effective and less toxic than free chemotherapeutics in chemoradiotherapy. Our work highlights the importance and potential of nanoformulations of combination chemotherapy in chemoradiotherapy and cancer treatment. This approach can be translated clinically and it can have a significant impact on cancer treatment.

ICG-Loaded PEG-Modified Black Phosphorus Nanosheets for Fluorescence Imaging-Guided Breast Cancer Therapy.

Indocyanine green (ICG) has been used in various surgical navigation systems and plays an important role in intraoperative imaging diagnosis. However, the poor photostability and unsatisfactory tumor-targeting ability have limited its broad application prospects. In the decades, the construction of a nanodrug delivery system for tumor-targeting diagnosis and therapy has become a research hotspot. Black phosphorus nanosheets (BPNS), as a new kind of biodegradable nanomaterials, have the advantages of high loading capacity, good biocompatibility, tumor targeting, and photothermal effect over other two-dimensional (2D) reported nanomaterials. Herein, ICG-loaded poly(ethylene glycol) (PEG)-modified BPNS (ICG@BPNS-PEG) nanocomposites are constructed to improve the tumor-targeting capacity and guide photothermal therapy through real-time fluorescence imaging. In this study, ICG@BPNS-PEG nanocomposites with a suitable size (240 ± 28 nm) have been successfully constructed. The photostability of ICG@BPNS-PEG nanocomposites surpassed that of free ICG after four on-off cycles of near laser irradiation (NIR). Moreover, ICG@BPNS-PEG nanocomposites have enhanced photothermal conversion ability. The cellular uptake result through flow cytometry showed that ICG@BPNS-PEG nanocomposites could be swallowed easily owing to the suitable size and passive cellular uptake. In addition, the cytotoxicity evaluation of MCF-7, 4T1 breast cancer cells, and healthy RPE cells through the MTT assay demonstrated that ICG@BPNS-PEG nanocomposites have lower cytotoxicity and good cellular compatibility without irradiation. However, the cytotoxicity and live/dead staining proved that ICG@BPNS-PEG nanocomposites have satisfactory photothermal therapeutic effects when irradiated. In the 4T1-bearing mice model, the fluorescence imaging after intravenous injection of nanocomposites showed that ICG@BPNS-PEG nanocomposites have superior passive tumor targeting accumulation through the enhanced permeability and retention (EPR) effect compared with that of free ICG. Also, changes in tumor volume showed a remarkable tumor growth inhibition effect compared with other groups. Moreover, the results of hematoxylin-eosin (H&E) staining of major organs in 4T1-bearing mice also demonstrated that the nanocomposites have good biocompatibility. Therefore, the constructed ICG@BPNS-PEG nanocomposites have substantial potential in breast cancer therapy.