Dual-Site Biomimetic Cu/Zn-MOF for Atopic Dermatitis Catalytic Therapy via Suppressing FcγR-Mediated Phagocytosis.

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease that carries a significant global economic burden. Elevated levels of reactive oxygen species (ROS) have been recognized as contributing to AD exacerbation, making them a potential therapeutic target for AD treatment. Here, we introduce a dual-site biomimetic copper/zinc metal-organic framework (Cu/Zn-MOF) featuring four types of enzyme-like activities for AD treatment via suppressing the Fcγ receptor (FcγR)-mediated phagocytosis signal by mimicking the bimetallic sites of natural copper-zinc superoxide dismutase (CuZn-SOD). Interestingly, the neighboring Cu and Zn sites in both Cu/Zn-MOF and CuZn-SOD are at similar distances of ∼5.98 and ∼6.3 Šfrom each other, respectively, and additionally, both Cu and Zn sites are coordinated to nitrogen atoms in both structures, and the coordinating ligands to Cu and Zn are both imidazole rings. Cu/Zn-MOF exhibits remarkable SOD-like activity as well as its glutathione peroxidase (GPx)-, thiol peroxidase (TPx)-, and ascorbate peroxidase (APx)-like activities to continuously consume ROS and mitigate oxidative stress in keratinocytes. Animal experiments show that Cu/Zn-MOF outperforms halcinonide solution (a potent steroid medication) in terms of preventing mechanical injuries, reducing cutaneous water loss, and inhibiting inflammatory responses while presenting favorable biosafety. Mechanistically, Cu/Zn-MOF functions through an FcγR-mediated phagocytosis signal pathway, decreasing the continuous accumulation of ROS in AD and ultimately suppressing disease progression. These findings will provide an effective paradigm for AD therapy and contribute to the development of two-site bionics (TSB).

Copper Deposition in Polydopamine Nanostructure to Promote Cuproptosis by Catalytically Inhibiting Copper Exporters of Tumor Cells for Cancer Immunotherapy.

Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.

Comparative analysis of clinical efficacy of stereotactic robot-guided puncture hematoma drainage and conventional puncture hematoma drainage in the treatment of intracerebral hemorrhage.

Objective: To compare and analyze the clinical effectiveness of conventional puncture hematoma drainage and stereotactic robot-guided puncture hematoma drainage in managing intracerebral hemorrhage. Methods: This is clinical comparative research. One hundred and twenty patients with the intracerebral hemorrhage who underwent puncture hematoma drainage in Baoding No.1 Central Hospital from March 2020 to May 2023 were included and were assigned into the control groups(n=60) and experimental groups(n=60) according to different treatment methods. The experimental group underwent stereotactic robot-guided puncture hematoma drainage, while the control group underwent conventional puncture hematoma drainage treatment. The duration and situation of surgery, levels of inflammatory factors, as well as preoperative and 1-week postoperative GCS scores and NIHSS scores were compared and analyzed between the two groups. Results: In comparison with the control group, the experimental group exhibited considerably less surgical duration(p=0.00), higher amount of intraoperative blood drainage and hematoma clearance rate(p=0.00). The experimental group possessed a substantially more reduced incidence of complications(10%) in comparison with the control group(25%), with a statistically substantial distinction(p=0.03). After therapy, CRP, TNF-a, and IL-6 degrees were considerably more decreased (p=0.00) in the experimental group in comparison with the control group, while GCS grades were considerably more prominent and NIHSS grades were considerably more reduced (p=0.00). Conclusion: Stereotactic robot-guided puncture hematoma drainage is a dependable and safe operative method to treat patients who had intracerebral hemorrhage, resulting in various benefits such as short length of operation, less injury, less inflammatory reaction, high hematoma clear efficiency and satisfactory recovery of neurological function.

Triptolide with hepatotoxicity and nephrotoxicity used in local delivery treatment of myocardial infarction by thermosensitive hydrogel.

Myocardial infarction (MI) resulting from coronary artery occlusion is the leading global cause of cardiovascular disability and mortality. Anti-inflammatory treatment plays an important role in MI treatment. Triptolide (TPL), as a Chinese medicine monomer, has a variety of biological functions, including anti-inflammatory, anti-tumor, and immunoregulation. However, it has been proved that TPL is poorly water soluble, and has clear hepatotoxicity and nephrotoxicity, which seriously limits its clinical application. Herein, we designed a long-acting hydrogel platform (TPL@PLGA@F127) for MI treatment by intramyocardial injection. First, we found that the inflammatory response and immune regulation might be the main mechanisms of TPL against MI by network pharmacology. Subsequently, we prepared the hydrogel platform (TPL@PLGA@F127) and tested its effects and toxicity on normal organs in the early stage of MI (3 days after MI-operation). The results showed that TPL@PLGA@F127 could not only promote "repair" macrophages polarization (to M2 macrophage) by day 3 after MI, but also has a long-lasting anti-inflammatory effect in the later stage of MI (28 days after MI-operation). Additionally, we proved that TPL@PLGA@F127 could attenuate the toxicity of TPL by releasing it more slowly and stably. Finally, we observed the long-term effects of TPL@PLGA@F127 on MI and found that it could improve cardiac function, depress the myocardial fibrosis and protect the cardiomyocytes. In summary, this study indicated that TPL@PLGA@F127 could not only enhance the therapeutic effects of TPL on MI, but also attenuate the hepatotoxicity and nephrotoxicity, which established a strong foundation for the clinical application of TPL for MI.

CaCO3 powder-mediated biomineralization of antigen nanosponges synergize with PD-1 blockade to potentiate anti-tumor immunity.

Antigen self-assembly nanovaccines advance the minimalist design of therapeutic cancer vaccines, but the issue of inefficient cross-presentation has not yet been fully addressed. Herein, we report a unique approach by combining the concepts of "antigen multi-copy display" and "calcium carbonate (CaCO3) biomineralization" to increase cross-presentation. Based on this strategy, we successfully construct sub-100 nm biomineralized antigen nanosponges (BANSs) with high CaCO3 loading (38.13 wt%) and antigen density (61.87%). BANSs can be effectively uptaken by immature antigen-presenting cells (APCs) in the lymph node upon subcutaneous injection. Achieving efficient spatiotemporal coordination of antigen cross-presentation and immune effects, BANSs induce the production of CD4+ T helper cells and cytotoxic T lymphocytes, resulting in effective tumor growth inhibition. BANSs combined with anti-PD-1 antibodies synergistically enhance anti-tumor immunity and reverse the tumor immunosuppressive microenvironment. Overall, this CaCO3 powder-mediated biomineralization of antigen nanosponges offer a robust and safe strategy for cancer immunotherapy.

Acidic and hypoxic tumor microenvironment regulation by CaO2-loaded polydopamine nanoparticles.

Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO2)-loaded nanostructure that can play a role of "one stone kill two birds", i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO2 loaded nanostructure. Specifically, CaO2-loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO2@mPDA-SH) can gradually accumulate in a tumor site. CaO2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO2@mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.

A comparative study on the efficacy of robot of stereotactic assistant and frame-assisted stereotactic drilling, drainage for intracerebral hematoma in patients with hypertensive intracerebral hemorrhage.

Objectives: To compare the clinical efficacy of robot of stereotactic assistant (ROSA) and frame-assisted stereotactic drilling and drainage for intracerebral hematoma in hypertensive intracerebral hemorrhage (HICH). Methods: A total of 142 patients with HICH treated in Baoding First Central Hospital from January 2018 to January 2020 were selected and divided into two groups using a random number table. The ROSA group was treated with a robot of stereotactic assistant, while the frame group underwent frame-assisted stereotactic drilling and drainage for intracerebral hematoma. Surgical duration, postoperative extubation time and complications were compared between the two groups. Venous blood (5 mL) was collected before and three days after surgery. The levels of inflammatory factors [tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6)], as well as neurological function indexes [neuron-specific enolase (NSE), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)] were detected by enzyme-linked immunosorbent assay. Results: The surgical duration, postoperative extubation time, and incidences of infection and postoperative rehemorrhage in the ROSA group were lower than those in the frame group (P < 0.05). In the ROSA group, postoperative TNF-α, hs-CRP, IL-6 and NSE levels were significantly lower while NGF and BDNF levels were higher than those in the frame group (all P < 0.05). Conclusion: Compared with frame-assisted stereotactic drilling and drainage for intracerebral hematoma, ROSA in HICH treatment shortens the surgical duration and postoperative extubation time, reduces the risks of infection and rehemorrhage and decreases inflammatory level, which is helpful for the recovery of neurological function.

Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition.

Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a "lactate treatment plant" (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.

Application evaluation of intraoperative ultrasound combined with neuro electrophysiological detection in the spinal cord glioma surgery.

OBJECTIVE: To observe application values of intraoperative ultrasound combined with neuro electrophysiological detection in the spinal cord glioma surgery. METHODS: Sixty patients with spinal cord glioma hospitalized in Baoding First Central Hospital from January 2016 to January 2018 were selected, randomly divided into two groups by the random number table method, with 30 cases of each group. PASS software was used to calculate the sample size. The control group was treated with traditional microsurgery, while the experimental group was treated with intraoperative ultrasound combined with neuro electrophysiological testing. The operation time, intraoperative blood loss, postoperative hospital stays, degree of tumor resection, clinical efficacy, recovery of neurological function, recovery of health status, quality of life score, and 2-year recurrence rate of the two groups of patients were observed and compared. RESULTS: The operation time of the experimental group was longer than that of the control group, and the postoperative hospital stay was shorter than that of the control group. The complete tumor resection rate, complete remission rate and postoperative scale scores of the experimental group were significantly higher than those of the control group, while the recurrence rate within two years was significantly lower than that of the control group. The above differences were statistically significant (p<0.05). CONCLUSIONS: Intraoperative ultrasound combined with neuro-electrophysiological detection for spinal glioma has more adequate protection of nerve function, high clinical complete remission rate, more thorough tumor resection, and lower recurrence rate than traditional microsurgery, which is worthy of clinical application.

Nanoparticle reinforced bacterial outer-membrane vesicles effectively prevent fatal infection of carbapenem-resistant Klebsiella pneumoniae.

Infection resulting from carbapenem-resistant Klebsiella pneumoniae (CRKP) is an intractable clinical problem. Outer membrane vesicles (OMVs) from CRKP are believed to be potential vaccine candidates. However, their immune response remains elusive due to low structural stability and poor size homogeneity. In this study, hollow OMVs were reinforced internally by size-controlled BSA nanoparticles to obtain uniform and stable vaccines through hydrophobic interaction. The result showed that the BSA-OMV nanoparticles (BN-OMVs) were homogenous with a size around 100 nm and exhibited a core-shell structure. Remarkably, subcutaneous BN-OMVs vaccination mediated significantly higher CRKP specific antibody titers. The survival rate of the mice infected with a lethal dose of CRKP was increased significantly after BN-OMV immunization. The adoptive transfer experiment demonstrated that the protective effect of BN-OMVs was dependent on humoral and cellular immunity. This study demonstrated that the structure optimization improved the immune efficacy of OMVs for vaccine development against CRKP.

Delivery of microRNA-1 inhibitor by dendrimer-based nanovector: An early targeting therapy for myocardial infarction in mice.

Myocardial infarction (MI), known to be rapidly progressed and fatal, necessitates a timely and effective intervention particularly within golden 24 h. The crux is to develop a therapeutic agent that can early target the infarct site with integrated therapeutic capacity. Finding the AT1 receptor being most over-expressed at 24 h after MI, we developed a nanovector (AT1-PEG-DGL) anchored with AT1 targeting peptide, and simultaneously armed it with specific microRNA-1 inhibitor (AMO-1) to attenuate cardiomyocyte apoptosis. In vivo imaging after IV administration demonstrated that AT1-PEG-DGL quickly accumulated in the MI heart during the desired early period, significantly outperforming the control group without AT1 targeting. Most importantly, a pronounced in-vivo anti-apoptosis effect was observed upon a single IV injection. Apoptotic cell death in the infarct border zone was significantly decreased and the myocardial infarct size was reduced by 64.1% as compared with that in MI control group, promising for early MI treatment.

Theranostic vesicles based on bovine serum albumin and poly(ethylene glycol)-block-poly(L-lactic-co-glycolic acid) for magnetic resonance imaging and anticancer drug delivery.

Presented in this article is the preparation of a new theranostic vesicle which exhibits excellent in vitro and in vivo T1 magnetic resonance (MR) imaging contrast effect and good anticancer drug delivery ability. The theranostic vesicle has been easily prepared based on an amphiphilic biocompatible and biodegradable dibock copolymer, poly(ethylene glycol)-block-poly(l-lactic-co-glycolic acid) (PEG-b-PLGA) and bovine serum albumin-gadolinium (BSA-Gd) complexes. Dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-vis spectroscopy, and inductively coupled plasma atomic emission spectroscopy (ICP-AES) measurements confirmed the formation and physiological stability of BSA-Gd@PEG-b-PLGA vesicles. Furthermore, the in vitro and in vivo MR imaging experiments revealed their excellent T1-weighted MR imaging function. Red blood cell hemolysis and cytotoxicity experiments confirmed their good blood compatibility and low cytotoxicity. Doxorubicin (DOX) loading and release experiments indicated a more retarded release rate of DOX in those theranostic vesicles than sole PEG-b-PLGA nanoparticles without BSA. Overall, this new biocompatible and biodegradable vesicle shows promising potential in theranostic applications.

Engineering of a Pluronic F127 functionalized magnetite/graphene nanohybrid for chemophototherapy.

In this study, a multifunctional graphene based nanohybrid, termed as GN/Fe3O4/PF127, is engineered via a facile one-pot process consisting of simultaneous reduction of graphene oxide/Fe3O4 and subsequent assembly of Pluronic F127 (PF127) onto graphene nanosheets (GNs). The unique aromatic and planar structure of GNs allows the attachment of multiple functional components including MRI contrast agent (Fe3O4 nanoparticles) and an aromatic anticancer drug like doxorubicin (DOX), as well as PF127 coating which imparts physiological dispersivity and stability to the nanohybrid. The successful assembly process is revealed by TEM observation, size and FITR monitoring. In contrast with the primitive graphene or its oxide derivative, the resulting GN/Fe3O4/PF127 nanohybrids have shown high biological dispersion and MRI effect for diagnosis due to the incorporation of superparamagnetic Fe3O4 nanoparticles without evident cytotoxicity. Moreover, the GN/Fe3O4/PF127 nanohybrid exhibits a photothermal effect due to the considerable optical absorption in the near-infrared region of GNs. The GN/Fe3O4/PF127 nanohybrid could be a further platform for chemophototherapy assisted by the therapeutic DOX. Cellular toxicity assays indicated that the DOX-loaded GN/Fe3O4/PF127 nanohybrid showed a remarkable cytotoxicity to HeLa cells and the cytotoxic effect was intensified when subjected to photoirradiation. Confocal laser scanning microscopy (CLSM) and flow cytometric analysis (FCAS) revealed that the nanohybrid could be easily uptaken into HeLa cells.

Impact of Microsurgery and Postoperative Radiotherapy on Neurological Function in Intramedullary Spinal Cord Gliomas.

OBJECTIVE: To assess the clinical efficacy of combined microsurgery and postoperative radiotherapy for the treatment of intramedullary spinal gliomas and its impact on neurological function. STUDY DESIGN: An observational study. Place and Duration of the Study: Department of Neurosurgery, Baoding No.1 Central Hospital, Hebei, China, between January 2020 and 2023. METHODOLOGY: Sixty patients diagnosed with spinal cord intramedullary gliomas were divided equally into an experimental and control group. The control group received microsurgical treatment, and the experimental group received microsurgical treatment combined with postoperative radiotherapy. The treatment effectiveness, neurological function, and follow-up results of the two groups were compared. RESULTS: After treatment, the clinical efficacy of the experimental group treatment was significantly better than that of the control group (p <0.05). The National Institutes of Health Stroke Scale (NIHSS) scores were significantly lower, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30) scores were significantly higher in the experimental group than in the control group (p <0.05). The 1-3-year survival rate and median survival time of the experimental group were significantly higher than those of the control group (p <0.05). The incidence of complications was 3.33% in the experimental group and 6.67% in the control group, but the difference was not statistically significant (p >0.05). The postoperative recurrence rate was significantly lower in the experimental (0%) than in the control group (13.33%, p <0.05). CONCLUSION: Combined microsurgery and postoperative radiotherapy was found to be more effective than microsurgery alone. It was also more conducive to the recovery of neurological function and improved the patient's quality of life. KEY WORDS: Intramedullary spinal cord glioma, Microsurgery, Neurological function, Radiotherapy.

Simultaneous volatile fatty acids promotion and antibiotic resistance genes reduction in fluoranthene-induced sludge alkaline fermentation: Regulation of microbial consortia and cell functions.

The impact and mechanism of fluoranthene (Flr), a typical polycyclic aromatic hydrocarbon highly detected in sludge, on alkaline fermentation for volatile fatty acids (VFAs) recovery and antibiotic resistance genes (ARGs) transfer were studied. The results demonstrated that VFAs production increased from 2189 to 4272 mg COD/L with a simultaneous reduction of ARGs with Flr. The hydrolytic enzymes and genes related to glucose and amino acid metabolism were provoked. Also, Flr benefited for the enrichment of hydrolytic-acidifying consortia (i.e., Parabacteroides and Alkalibaculum) while reduced VFAs consumers (i.e., Rubrivivax) and ARGs potential hosts (i.e., Rubrivivax and Pseudomonas). Metagenomic analysis indicated that the genes related to cell wall synthesis, biofilm formation and substrate transporters to maintain high VFAs-producer activities were upregulated. Moreover, cell functions of efflux pump and Type IV secretion system were suppressed to inhibit ARGs proliferation. This study provided intrinsic mechanisms of Flr-induced VFAs promotion and ARGs reduction during alkaline fermentation.

Arginine-Nanoenzyme with Timely Angiogenesis for Promoting Diabetic Wound Healing.

The successful treatment of diabetic wounds requires strategies that promote anti-inflammation, angiogenesis, and re-epithelialization of the wound. Excessive oxidative stress in diabetic ulcers (DUs) inhibits cell proliferation and hinders timely vascular formation and macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2, resulting in a persistent inflammatory environment and a nonhealing wound. We designed arginine-nanoenzyme (FTA) with mimic-catalase and arginine-loading. 2,3,4-trihydroxy benzaldehyde and arginine (Arg) were connected by a Schiff base bond, and the nanoassembly of Arg to FTA was driven by the coordination force between a ferric ion and polyphenol and noncovalent bond force such as a hydrogen bond. FTA could remove excess reactive oxygen species at the wound site in situ and convert it to oxygen to improve hypoxia. Meanwhile, Arg was released and catalytically metabolized by NO synthase in M1 to promote vascular repair in the early phase. In the late phase, the metabolite of Arg catalyzed by arginase in M2 was mainly ornithine, which played a vital role in promoting tissue repair, which implemented angiogenesis timely and prevented hypertrophic scars. Mechanistically, FTA activated the cAMP signaling pathway combined with reducing inflammation and ameliorating angiogenesis, which resulted in excellent therapeutic effects on a DU mice model.

Nano-mechanical Immunoengineering: Nanoparticle Elasticity Reprograms Tumor-Associated Macrophages via Piezo1.

The mechanical properties of nanoparticles play a crucial role in regulating nanobiointeractions, influencing processes such as blood circulation, tumor accumulation/penetration, and internalization into cancer cells. Consequently, they have a significant impact on drug delivery and therapeutic efficacy. However, it remains unclear whether and how macrophages alter their biological function in response to nanoparticle elasticity. Here, we report on the nano-mechanical biological effects resulting from the interactions between elastic silica nanoparticles (SNs) and macrophages. The SNs with variational elasticity Young's moduli ranging from 81 to 837 MPa were synthesized, and it was demonstrated that M2 [tumor-associated macrophages (TAMs)] could be repolarized to M1 by the soft SNs. Additionally, our findings revealed that cell endocytosis, membrane tension, the curvature protein Baiap2, and the cytoskeleton were all influenced by the elasticity of SNs. Moreover, the mechanically sensitive protein Piezo1 on the cell membrane was activated, leading to calcium ion influx, activation of the NF-κB pathway, and the initiation of an inflammatory response. In vivo experiments demonstrated that the softest 81 MPa SNs enhanced tumor penetration and accumulation and repolarized TAMs in intratumoral hypoxic regions, ultimately resulting in a significant inhibition of tumor growth. Taken together, this study has established a cellular feedback mechanism in response to nanoparticle elasticity, which induces plasma membrane deformation and subsequent activation of mechanosensitive signals. This provides a distinctive "nano-mechanical immunoengineering" strategy for reprogramming TAMs to enhance cancer immunotherapy.

Arginine-assembly as NO nano-donor prevents the negative feedback of macrophage repolarization by mitochondrial dysfunction for cancer immunotherapy.

Repolarizing the tumor-associated macrophages (TAMs) towards the antitumoral M1-like phenotype has been a promising approach for cancer immunotherapy. However, the anti-cancer immune response is severely limited mainly by the repolarized M1-like macrophages belatedly returning to the M2-like phenotype (i.e., negative feedback). Inspired by nitric oxide (NO) effectively preventing repolarization of inflammatory macrophages in inflammatory diseases, herein, we develop an arginine assembly, as NO nano-donor for NO generation to prevent the negative feedback of the macrophage repolarization. The strategy is to first apply reversible tagging of hydrophobic terephthalaldehyde to create an arginine nano-assembly, and then load a toll-like receptor 7/8 agonist resiquimod (R848) (R848@Arg). Through this strategy, a high loading efficiency of 40 % for the arginine and repolarization characteristics for TAMs can be achieved. Upon the macrophage repolarization by R848, NO can be intracellularly generated from the released arginine by the upregulated inducible nitric oxide synthase. Mechanistically, NO effectively prevented the negative feedback of the repolarized macrophage by mitochondrial dysfunction via blocking oxidative phosphorylation. Notably, R848@Arg significantly increased the tumor inhibition ratio by 3.13-fold as compared to the free R848 by maintaining the M1-like phenotype infiltrating into tumor. The Arg-assembly as NO nano-donor provides a promising method for effective repolarization of macrophages.

A versatile multicomponent assembly via ß-cyclodextrin host-guest chemistry on graphene for biomedical applications.

A multi-component nanosystem based on graphene and comprising individual cyclodextrins at its surface is assembled, creating hybrid structures enabling new and important functionalities: optical imaging, drug storage, and cell targeting for medical diagnosis and treatment. These nanohybrids are part of a universal system of interchangeable units, capable of mutilple functionalities. The surface components, made of individual ß-cyclodextrin molecules, are the "hosts" for functional units, which may be used as imaging agents, for anti-cancer drug delivery, and as tumor-specific ligands. Specifically, individual ß-cyclodextrin (ß-CD), with a known capability to host various molecules, is considered a module unit that is assembled onto graphene nanosheet (GNS). The cyclodextrin-functionalized graphene nanosheet (GNS/ß-CD) enables "host-guest" chemistry between the nanohybrid and functional "payloads". The structure, composition, and morphology of the graphene nanosheet hybrid have been investigated. The nanohybrid, GNS/ß-CD, is highly dispersive in various physiological solutions, reflecting the high biostability of cyclodextrin. Regarding the host capability, the nanohybrid is fully capable of selectively accommodating various biological and functional agents in a controlled fashion, including the antivirus drug amantadine, fluorescent dye [5(6)-carboxyfluorescein], and Arg-Gly-Asp (RGD) peptide-targeting ligands assisted by an adamantine linker. The loading ratio of 5(6)-carboxyfluorescein is as high as 110% with a drug concentration of 0.45 mg mL(-1). The cyclic RGD-functionalized nanohybrid exhibits remarkable targeting for HeLa cells.