A polymer nanogel-based therapeutic nanovaccine for prophylaxis and direct treatment of tumors via a full-cycle immunomodulation.

Construction of a cancer nanovaccine that can simultaneously activate immune cells and exert efficient tumor treatment still remains a challenge. Herein, we showcase a proof-of-concept demonstration of an advanced therapeutic nanovaccine formulation based on poly(N-vinylcaprolactam) nanogels (NGs) which were loaded with manganese dioxide (MnO2), the sonosensitizer chlorin e6 (Ce6), and the immune adjuvant cyclic GMP-AMP (cGAMP). The gels were furthermore coated with apoptotic cancer cell membranes (AM). On the one hand, the AM promoted the recognition of NGs by antigen presenting cells (APCs) in lymph nodes due to their enhanced immunogenicity, then the loaded Mn and cGAMP could mature APCs via stimulator of interferon genes (STING) activation for triggering immunity to prevent tumor growth. On the other hand, the NGs could selectively release Mn2+ for hydroxyl radical production and Ce6 to generate single oxygen under ultrasound irradiation of tumors, respectively, thereby exerting local chemodynamic/sonodynamic therapy to induce immunogenic cell death (ICD). Moreover, the Mn2+ could also activate STING in tumors to synergize with ICD for potentiated immune responses. Overall, the biomimetic NG-based therapeutic nanovaccine could directly evoke immune system, and also conduct local tumor treatment to further activate ICD, thus realizing a full-cycle immunomodulation (tumor killing for ICD/antigen production, and tumor cells/APCs immune activation) to tackle bilateral tumor growth.

Synthesis and Characterization of Copper-Crosslinked Carbon Dot Nanoassemblies for Efficient Macrophage Manipulation.

Nanomedicines loaded in macrophages (MAs) can actively target tumors without dominantly relying on the enhanced permeability and retention (EPR) effect, making them effective for treating EPR-deficient malignancies. Herein, copper-crosslinked carbon dot clusters (CDCs) are synthesized with both photodynamic and chemodynamic functions to manipulate MAs, aiming to direct the MA-mediated tumor targeting. First, green fluorescent CDs (g-CDs) are prepared by a one-step hydrothermal method. Subsequently, the g-CDs are complexed with divalent copper ions to form copper-crosslinked CDCs (g-CDCs/Cu), which are incubated with MAs for their manipulation. Experimental results revealed that the prepared g-CDCs/Cu displayed good aqueous dispersibility and fluorescent emission properties. The nanoassemblies can be activated to deplete the overexpressed glutathione (GSH) and generate reactive oxygen species (ROS) in the presence of laser irradiation through the combined Cu-mediated chemodynamic therapy and CD-mediated photodynamic therapy. Furthermore, the ROS produced in MAs enabled polarization of MAs to antitumor M1 phenotype, suggesting the future potential use to reverse the immunosuppressive tumor microenvironment. These results obtained from the current study suggest a significant potential to develop g-CDCs/Cu for GSH depletion, ROS generation, and MA M1 polarization as a theransotic agent to tackle cancer.

A functionalized cell membrane biomimetic nanoformulation based on layered double hydroxide for combined tumor chemotherapy and sonodynamic therapy.

The development of nanoformulations with simple compositions that can exert targeted combination therapy still remains a great challenge in the area of precision cancer nanomedicine. Herein, we report the design of a multifunctional nanoplatform based on methotrexate (MTX)-loaded layered double hydroxide (LDH) coated with chlorin e6 (Ce6)-modified MCF-7 cell membranes (CMM) for combined chemo/sonodynamic therapy of breast cancer. LDH nanoparticles were in situ loaded with MTX via coprecipitation, and coated with CMM that were finally functionalized with phospholipid-modified Ce6. The created nanoformulation of LDH-MTX@CMM-Ce6 displays good colloidal stability under physiological conditions and can release MTX in a pH-dependent manner. We show that the formulation can homologously target breast cancer cells, and induce their significant apoptosis through arresting the cell cycle via cooperative MTX-based chemotherapy and ultrasound (US)-activated sonodynamic therapy. The assistance of US can not only trigger sonosensitizer Ce6 to produce reactive oxygen species, but also enhance the cellular uptake of LDH-MTX@CMM-Ce6 via an acoustic cavitation effect. Upon intravenous injection and US irradiation, LDH-MTX@CMM-Ce6 displays an admirable antitumor performance towards a xenografted breast tumor mouse model. Furthermore, the modification of Ce6 on the CMM endows the LDH-based nanoplatform with fluorescence imaging capability. The developed LDH-based nanoformulation here provides a general intelligent cancer nanomedicine platform with simple composition and homologous targeting specificity for combined chemo/sonodynamic therapy and fluorescence imaging of tumors.

Biomimetic Dual-Target Theranostic Nanovaccine Enables Magnetic Resonance Imaging and Chemo/Chemodynamic/Immune Therapy of Glioma.

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

Natural alkaloids from Dicranostigma leptopodum (Maxim.) Fedde and their G5. NHAc-PBA dendrimer-alkaloid complexes for targeting chemotherapy in breast cancer MCF-7 cells.

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 µM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 µM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 µM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.

Hyperbranched Polymer-Based Vaccines for Cancer Immunotherapy.

Recently, several immunotherapeutic strategies are extensively studied and entered clinical investigation, suggesting their potential to lead a new generation of cancer therapy. Particularly, a cancer vaccine that combines tumor-associated antigens and immune adjuvants with a nanocarrier holds huge promise for inducing specific antitumor immune responses. Hyperbranched polymers, such as dendrimers and branched polyethylenimine (PEI) possessing abundant positively charged amine groups and inherent proton sponge effect are ideal carriers of antigens. Much effort is devoted to design dendrimer/branched PEI-based cancer vaccines. Herein, the recent advances in the design of dendrimer/branched PEI-based cancer vaccines for immunotherapy are reviewed. The future perspectives with regard to the development of dendrimer/branched PEI-based cancer vaccines are also briefly discussed.

How does market-oriented allocation of industrial land affect carbon emissions? Evidence from China.

Industrial land serves as the fundamental basis for urban economic development and significantly contributes to carbon emissions. Effective market mechanisms are crucial for reducing carbon emissions. As such, investigating the impact of market-oriented allocation of industrial land (MAIL) on carbon emissions and its pathways is of substantial practical importance for global low-carbon development. This study constructs a theoretical framework examining the influence of MAIL on carbon emissions, focusing on 285 Chinese cities from 2003 to 2020. The spatial econometric model is employed to analyze the impact of MAIL on carbon emissions. The results show that: first, from a national perspective, MAIL not only reduces carbon emissions within a region but also in neighboring regions. Higher MAIL leads to more effective carbon emission reductions, which are persistent and hysteresis in time. Path analysis demonstrates that MAIL reduces carbon emissions by promoting industrial upgrading and technological innovation. Second, there are differences in the timeliness of carbon emission reduction effects in cities of different scales and regions. For cities of different scales, the carbon reduction effect of MAIL is more stable in large and medium cities compared to megacities and small cities, but in the short term, MAIL will hinder the industrial upgrading of megacities and thus is not conducive to carbon reduction. For different regional cities, the carbon reduction effect of MAIL is more stable in other regions except northeast region, and in the short term, MAIL will inhibit technological innovation in northeast region, which is not conducive to carbon reduction. Consequently, it is essential not only to design a top-level reform plan for MAIL in China but also to establish differentiated reform policies for MAIL, tailored to the unique characteristics of cities with different scales and regions, to effectively reduce carbon emissions.

Ultrasound-enhanced theranostics of orthotopic breast cancer through a multifunctional core-shell tecto dendrimer-based nanomedicine platform.

Design of multifunctional nanoplatforms combined with ultrasound-targeted microbubble destruction (UTMD) technology for enhanced tumor accumulation is feasible to solve the bottleneck of theranostics. Herein, we present the development of zwitterion-modified gadolinium (Gd)-chelated core-shell tecto dendrimers (CSTDs) as a nanomedicine platform (PCSTD-Gd) for enhanced magnetic resonance (MR) imaging-guided chemo-gene therapy of orthotopic breast cancer with the assistance of UTMD. In our design, CSTDs synthesized via supramolecular recognition of ß-cyclodextrin and adamantane were covalently linked with tetraazacyclododecane tetraacetic acid-Gd(III) chelators, modified with 1,3-propane sultone to achieve good protein-resistance property, and used for co-delivery of an microRNA 21 inhibitor (miR 21i) and an anticancer drug doxorubicin (DOX). The overall design is quite advantageous and cooperative. The CSTDs with a greater size than single-generation core dendrimers have amplified the enhanced permeability and retention effect for better passive tumor targeting, with a larger r1 relaxivity for sensitive MR imaging and serum-enhanced gene delivery efficiency due to the better compaction ability as well as the protein resistance ability, and with larger interior space for improved drug loading. Through the unique design and the assistance of UTMD, the obtained PCSTD-Gd/DOX/miR 21i polyplexes enable enhanced MR imaging-guided combined chemo-gene therapy of an orthotopic breast cancer model in vivo.

Phosphorous Dendron Micelles as a Nanomedicine Platform for Cooperative Tumor Chemoimmunotherapy via Synergistic Modulation of Immune Cells.

Design of effective nanomedicines to modulate multiple immune cells to overcome the immune-suppressive tumor microenvironment is desirable to improve the overall poor clinical outcomes of immunotherapy. Herein, a nanomedicine platform is reported based on chemotherapeutic drug doxorubicin (DOX)-loaded phosphorus dendron micelles (M-G1-TBPNa@DOX, TBP, tyramine bearing two dimethylphosphonate) with inherent immunomodulatory activity for synergistic tumor chemoimmunotherapy. The M-G1-TBPNa@DOX micelles with good stability and a mean particle size of 86.4 nm can deliver DOX to solid tumors to induce significant tumor cell apoptosis and immunogenic cell death (ICD). With the demonstrated intrinsic activity of M-G1-TBPNa that can promote the proliferation of natural killer (NK) cells, the ICD-resulted maturation of dendritic cells of the DOX-loaded micelles, and the combination of anti-PD-L1 antibody, the synergistic modulation of multiple immune cells through NK cell proliferation, recruitment of tumor-infiltrating NK cells and cytotoxic T cells, and decrease of regulatory T cells for effective tumor chemoimmunotherapy with strong antitumor immunity and immune memory effect for effective prevention of lung metastasis are demonstrated. The developed phosphorous dendron micelles may hold great promise to be used as an advanced nanomedicine formulation for synergistic modulation of multiple immune cells through NK cell proliferation for effective chemoimmunotherapy of different tumor types.

Chemotherapy Mediated by Biomimetic Polymeric Nanoparticles Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long-term antitumor immunity still remains to be an extreme challenge. Herein, the design of an advanced redox-responsive nanomedicine formulation based on phosphorus dendrimer-copper(II) complexes (1G3 -Cu)- and toyocamycin (Toy)-loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM) are reported. The designed GCT@CM NPs with a size of 210 nm are stable under physiological conditions but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co-loading of 1G3 -Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G3 -Cu-induced mitochondrial dysfunction and Toy-mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G3 -Cu render the GCT@CM NPs with homotypic targeting and T1 -weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP-mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy-potentiated immunotherapy of different tumor types through different mechanisms or synergies.

Disturbed boundaries extraction in coal-grain overlap areas with high groundwater levels using UAV-based visible and multispectral imagery.

With high groundwater levels, coal-grain overlap areas (CGOAs) are vulnerable to subsidence and water logging during mining activities, thereby impacting crop yields adversely. Such damage requires full reports of disturbed boundaries for agricultural reimbursement and ongoing reclamation, but because direct measurements are difficult in such cases because of vast unreachable areas, it is necessary to be able to identify out-of-production boundaries (OBs) and reduced-production boundaries (RBs) in the corresponding region. In this study, an OB was extracted by setting a threshold via the characteristics of the cultivated-land elevation based on a digital surface model and a digital orthophoto map generated using an unmanned aerial vehicle (UAV). Meanwhile, the above-ground biomass (AGB), the soil plant analysis development (SPAD) value of chlorophyll contents, and leaf area index (LAI) were used to select the appropriate vegetation indices (VIs) to produce a reduced-production map (RM) based on power regression (PR), exponential regression (ER), multiple linear regression (MR), and random forest (RF) algorithms. Finally, an improved Otsu segmentation algorithm was used to extract mild and severe RBs. The results showed the following. (1) Crop growth heights in a typical ponding basin of the CGOA rendered a fast and efficient approach to distinguishing the OB. (2) In subsequent sample modeling, the red-edge microwave VI (MVIredge), the normalized difference VI (NDVI), and the red-edge modified simple ratio index (MSRredge) combined with RF were shown to be optimal estimators for AGB (R2 = 0.83, RMSE = 0.114 kg·m-2); the red-edge NDVI (NDVIredge), the green NDVI (GNDVI), and the red-edge chlorophyll index (CIredge) acted as strong tools in SPAD prediction using RF (R2 = 0.83, RMSE = 0.152 SPAD); the red-edge modified simple ratio index (MSRredge), the GNDVI, and the green chlorophyll index (CIgreen) via MR were more accurate when conducting the inversion of LAI (R2 = 0.88, RMSE = 1.070). (3) With the improved Otsu algorithm, multiple degrees of RB extraction can be achieved in RM. This study provides reference methods and theoretical support for determining disturbed boundaries in CGOAs with high groundwater levels for further agricultural compensation and reclamation processes.

Fibronectin-Coated Metal-Phenolic Networks for Cooperative Tumor Chemo-/Chemodynamic/Immune Therapy via Enhanced Ferroptosis-Mediated Immunogenic Cell Death.

The development of nanomedicine formulations to overcome the disadvantages of traditional chemotherapeutic drugs and integrate cooperative theranostic modes still remains challenging. Herein, we report the facile construction of a multifunctional theranostic nanoplatform based on doxorubicin (DOX)-loaded tannic acid (TA)-iron (Fe) networks (for short, TAF) coated with fibronectin (FN) for combination tumor chemo-/chemodynamic/immune therapy under the guidance of magnetic resonance (MR) imaging. We show that the DOX-TAF@FN nanocomplexes created through in situ coordination of TA and Fe(III) and physical coating with FN have a mean particle size of 45.0 nm, are stable, and can release both DOX and Fe in a pH-dependent manner. Due to the coexistence of the TAF network and DOX, significant immunogenic cell death can be caused through enhanced ferroptosis of cancer cells via cooperative Fe-based chemodynamic therapy and DOX chemotherapy. Through further treatment with programmed cell death ligand 1 antibody for an immune checkpoint blockade, the tumor treatment efficacy and the associated immune response can be further enhanced. Meanwhile, with FN-mediated targeting, the DOX-TAF@FN platform can specifically target tumor cells with high expression of αvß3 integrin. Finally, the TAF network also enables the DOX-TAF@FN to have an r1 relaxivity of 6.1 mM-1 s-1 for T1-weighted MR imaging of tumors. The developed DOX-TAF@FN nanocomplexes may represent an updated multifunctional nanosystem with simple compositions for cooperative MR imaging-guided targeted chemo-/chemodynamic/immune therapy of tumors.

Engineered cancer cell membranes: An emerging agent for efficient cancer theranostics.

For efficient cancer theranostics, surface modification of nanomaterials plays an important role in improving targeting ability and reducing the non-specific interactions with normal tissues. Recently, the biomimetic technology represented by coating of cancer cell membranes (CCMs) has been regarded as a promising method to strengthen the biocompatibility and targeting specificity of nanomaterials. Furthermore, the engineered CCMs (ECCMs) integrated with the natural biological properties of CCMs and specific functions from other cells or proteins have offered more possibilities in the field of cancer theranostics. Herein, the recent progresses in the design and preparation of ECCMs are summarized, and the applications of ECCMs in targeting delivery, activation of immunity, and detection of circulating tumor cells are reviewed. Finally, the current challenges and future perspectives with regard to the development of ECCMs are briefly discussed.

Metal-Phenolic-Network-Coated Dendrimer-Drug Conjugates for Tumor MR Imaging and Chemo/Chemodynamic Therapy via Amplification of Endoplasmic Reticulum Stress.

Amplification of endoplasmic reticulum stress (ERS) to realize enhanced cancer therapy has been considered to be unique in current cancer nanomedicine design. Herein, the design of metal-phenolic-network-coated dendrimer-drug conjugates as a novel theranostic nanoplatform based on ERS amplification is reported. In the design, acetylated generation-5 poly(amidoamine) dendrimers are conjugated with an ERS drug, toyocamycin (Toy), through the attached phenylboronic acid moiety, and coated with an iron (Fe)-tannic acid (TF) network. The generated nanocomplexes with a size of 50.2 nm are stable under the physiological environment, and can rapidly release Toy under the tumor microenvironment due to the pH- and reactive-oxygen-species-responsive boronic ester bonds to effectively inhibit the ERS-mediated cancer cell adaptation. Meanwhile, the coated TF network enables the nanocomplexes to generate cytotoxic hydroxyl radicals through a Fenton reaction, amplifying the ERS for improved chemo/chemodynamic therapy of cancer cells in vitro and a xenografted breast tumor model in vivo. Moreover, the coating of TF also renders the complexes with an eminent r1 relaxivity for in vivo T1 -weighted tumor magnetic resonance imaging. The created intelligent nanocomplexes may represent an advanced nanomedicine formulation uniquely integrated with a metal-phenolic network and dendrimer nanotechnology for imaging-guided cancer therapy through ERS amplification.

"Cluster Bomb" Based on Redox-Responsive Carbon Dot Nanoclusters Coated with Cell Membranes for Enhanced Tumor Theranostics.

Designing intelligent stimuli-responsive nanoplatforms that are integrated with a biological membrane system and nanomaterials to realize efficient imaging and therapy of tumors still remains to be challenging. Herein, we report a unique strategy to prepare redox-responsive yellow fluorescent carbon dot nanoclusters (y-CDCs) loaded with anticancer drug doxorubicin (DOX) and coated with the cancer cell membrane (CCM) for precision fluorescence imaging and homologous targeting chemotherapy of tumors. The y-CDs with a size of 7.2 nm were first synthesized via a hydrothermal method and crosslinked to obtain redox-responsive y-CDCs with a size of 150.0 nm. The formulated y-CDCs were physically loaded with DOX with an efficiency of up to 81.0% and coated with CCM to endow them with antifouling properties, immune escape ability to escape from macrophage uptake, and homologous targeting capability to cancer cells. Within the reductive tumor microenvironment, the y-CDCs with quenched fluorescence can dissociate to form single y-CDs with recovered fluorescence and improved tumor penetration ability and simultaneously release DOX from the "cluster bomb", thus realizing efficient targeted tumor fluorescence imaging and chemotherapy. The designed y-CDCs/DOX@CCM may represent an updated nanomedicine formulation based on CDs for improved theranostics of different types of tumors.

Construction of Poly(amidoamine) Dendrimer/Carbon Dot Nanohybrids for Biomedical Applications.

Design of intelligent hybrid nanoparticles that can integrate diagnosis and therapy components plays an important role in the field of nanomedicine. Poly(amidoamine) (PAMAM) dendrimers possessing a unique architecture and tunable functional groups have been widely developed for various biomedical applications. Carbon dots (CDs) are considered as a promising fluorescence probe or drug delivery system due to their stable fluorescence property and excellent biocompatibility. The distinctive merits of PAMAM dendrimers and CDs are amenable for them to be constructed as perfect nanohybrids for different biomedical applications, in particular for cancer nanomedicine. Here, the recent advances in the construction of PAMAM dendrimer/CD nanohybrids for diverse biomedical applications, in particular for sensing and cancer theranostics are summarized. Finally, the future perspectives of the PAMAM dendrimer/CD nanohybrids are also briefly discussed.