Tailoring therapeutics via a systematic beneficial elements comparison between photosynthetic bacteria-derived OMVs and extruded nanovesicles.

Photosynthetic bacteria (PSB) has shown significant potential as a drug or drug delivery system owing to their photothermal capabilities and antioxidant properties. Nevertheless, the actualization of their potential is impeded by inherent constraints, including their considerable size, heightened immunogenicity and compromised biosafety. Conquering these obstacles and pursuing more effective solutions remains a top priority. Similar to extracellular vesicles, bacterial outer membrane vesicles (OMVs) have demonstrated a great potential in biomedical applications. OMVs from PSB encapsulate a rich array of bioactive constituents, including proteins, nucleic acids, and lipids inherited from their parent cells. Consequently, they emerge as a promising and practical alternative. Unfortunately, OMVs have suffered from low yield and inconsistent particle sizes. In response, bacteria-derived nanovesicles (BNVs), created through controlled extrusion, adeptly overcome the challenges associated with OMVs. However, the differences, both in composition and subsequent biological effects, between OMVs and BNVs remain enigmatic. In a groundbreaking endeavor, our study meticulously cultivates PSB-derived OMVs and BNVs, dissecting their nuances. Despite minimal differences in morphology and size between PSB-derived OMVs and BNVs, the latter contains a higher concentration of active ingredients and metabolites. Particularly noteworthy is the elevated levels of lysophosphatidylcholine (LPC) found in BNVs, known for its ability to enhance cell proliferation and initiate downstream signaling pathways that promote angiogenesis and epithelialization. Importantly, our results indicate that BNVs can accelerate wound closure more effectively by orchestrating a harmonious balance of cell proliferation and migration within NIH-3T3 cells, while also activating the EGFR/AKT/PI3K pathway. In contrast, OMVs have a pronounced aptitude in anti-cancer efforts, driving macrophages toward the M1 phenotype and promoting the release of inflammatory cytokines. Thus, our findings not only provide a promising methodological framework but also establish a definitive criterion for discerning the optimal application of OMVs and BNVs in addressing a wide range of medical conditions.

Wound microenvironment self-adaptive all-in-one hydrogel for rapid healing of the diabetic wound.

The natural healing of diabetic wounds is collectively impeded by multiple factors, including hyperglycemia, angiogenesis disorders, acute oxidative stress, and prolonged inflammation. Although considerable effort has been devoted to solving these problems, the treatment of diabetic wounds remains a major clinical obstacle. In light of this, we developed an innovative wound microenvironment self-adaptive hydrogel to promote the healing of diabetic wounds. The hydrogel was constructed by the crosslinking of 3-aminobenzeneboronic acid (PBA)-modified gelatin (Gel) and polyvinyl alcohol (PVA) by borate ester bonds, which showed high responsiveness to glucose. Meanwhile, the liposomes that encapsulated metformin, L-arginine, and L(+)-ascorbic acid were incorporated into the hydrogel framework. The hydrogel@lipo composite demonstrated shape adaptability, glucose responsiveness, and all-in-one capability, thereby effectively improving the intricate microenvironment of diabetic wounds. In vitro and in vivo experiments demonstrated the ability of hydrogel@lipo to mitigate oxidative stress, enhance angiogenesis, and attenuate inflammatory responses. Consequently, the hydrogel@lipo could accelerate diabetic wound healing (within two weeks). The cumulative findings strongly suggest the potential of hydrogel@lipo as a highly promising therapeutic dressing for advancing diabetic wound recovery.

Effects of Different Heat Treatments on Yak Milk Proteins on Intestinal Microbiota and Metabolism.

Dairy products are susceptible to modifications in protein oxidation during heat processing, which can lead to changes in protein function, subsequently affecting intestinal health. Despite being a unique nutritional source, yak milk has not been thoroughly examined for the effects of its oxidized proteins on intestinal microbiota and metabolism. Hence, this study employed different heat treatment methods (low-temperature pasteurization, high-temperature pasteurization, and high-temperature sterilization) to induce oxidation in yak milk proteins. The study then assessed the degree of oxidation in these proteins and utilized mice as research subjects. Using metagenomics and metabolomics methods, this study examined the structure of intestinal microbial communities and metabolic products in mice consuming oxidized yak milk. The results showed a decrease in carbonyl and total thiol contents of yak milk proteins after different heat treatments, indicating that heat treatment causes oxidation in yak milk proteins. Metagenomic analysis of mouse intestinal microbiota revealed significant changes in 66 genera. In the high-temperature sterilization group (H), key differential genera included Verrucomicrobiales, Verrucomicrobiae, Akkermansiaceae, and 28 others. The high-temperature pasteurization group (M) mainly consisted of Latilactobacillus, Bacillus, and Romboutsia. The low-temperature pasteurization group (L) primarily comprised of Faecalibacterium, Chaetomium, Paenibacillaceae, Eggerthella, Sordariales, and 33 others. Functionally, compared to the control group (C), the H group upregulated translation and energy metabolism functions, the L group the M group significantly upregulated metabolism of other amino acids, translation, and cell replication and repair functions. Based on metabolomic analysis, differential changes in mouse metabolites could affect multiple metabolic pathways in the body. The most significantly affected metabolic pathways were phenylalanine metabolism, vitamin B6 metabolism, steroid hormone biosynthesis, and pantothenate and CoA biosynthesis. The changes were similar to the functional pathway analysis of mouse metagenomics, affecting amino acid and energy metabolism in mice. In summary, moderate oxidation of yak milk proteins exhibits a positive effect on mouse intestinal microbiota and metabolism. In conclusion, yak milk has a positive effect on mouse intestinal microflora and metabolism, and this study provides a scientific basis for optimizing dairy processing technology and further developing and applying yak milk.

Modulating the Coordination Environment of Carbon-Dot-Supported Fe Single-Atom Nanozymes for Enhanced Tumor Therapy.

Herein, carbon dot (CD)-supported Fe single-atom nanozymes with high content of pyrrolic N and ultrasmall size (ph-CDs-Fe SAzyme) are fabricated by a phenanthroline-mediated ligand-assisted strategy. Compared with phenanthroline-free nanozymes (CDs-Fe SAzyme), ph-CDs-Fe SAzyme exhibit higher peroxidase (POD)-like activity due to their structure similar to that of ferriporphyrin in natural POD. Aberration-corrected high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and X-ray absorption fine structure spectroscopy (XAFS) analyses show that metal Fe is dispersed in ph-CDs-Fe SAzyme as single atoms. Steady-state kinetic studies show that the maximum velocity (Vmax ) and turnover number (kcat ) of H2 O2  homolytic cleavage catalyzed by ph-CDs-Fe SAzyme are 3.0 and 6.2 more than those of the reaction catalyzed by CDs-Fe SAzyme. Density functional theory (DFT) calculations show that the energy barrier of the reaction catalyzed by ph-CDs-Fe SAzyme is lower than that catalyzed by CDs-Fe SAzyme. Antitumor efficacy experiments show that ph-CDs-Fe SAzyme can efficiently inhibit the growth of tumor cells both in vitro and in vivo by synergistic chemodynamic and photothermal effects. Here a new paradigm is provided for the development of efficient antitumor therapeutic approaches based on SAzyme with POD-like activity.

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid.

Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, different strategies to efficiently deliver nucleic acid delivery from LNPs are concluded and their mechanisms are investigated. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, the issues that are necessary to be approached in the clinical translation of LNPs are discussed, which it is hoped will shed light on the development of LNP nucleic acid drugs.

A transdermal drug delivery system based on dissolving microneedles for boron neutron capture therapy of melanoma.

Boron neutron capture therapy (BNCT) is a promising therapy for malignant tumors that requires selective and high concentrations of 10B accumulation in tumor cells. Despite ongoing developments in novel boron agents and delivery carriers, the progress and clinical application of BNCT is still restricted by the low 10B accumulation and tumor-to-normal tissue (T/N) ratio. Herein, a dissolving microneedle-based transdermal drug delivery system was specifically designed for BNCT in a mouse model of melanoma. By incorporating fructose-BPA (F-BPA) into PVA microneedle tips, this system successfully delivered sufficient F-BPA into the melanoma site after the application of only two patches. Notably, the T/N ratio achieved through the treatment combining PVA/F-BPA MNs with BNCT (PVA/F-BPA MNs-BNCT) surpassed 93.16, signifying a great improvement. Furthermore, this treatment approach effectively inhibited tumor growth and significantly enhanced the survival rate of the mice. In brief, our study introduces a novel, simple, and efficient administration strategy for BNCT, opening new possibilities for the design of nanomedicine for BNCT.

Redirecting Antigens by Engineered Photosynthetic Bacteria and Derived Outer Membrane Vesicles for Enhanced Cancer Immunotherapy.

Significant strides have been made in the development of cancer vaccines to combat malignant tumors. However, the natural immunosuppressive environment within tumors, known as the tumor microenvironment (TME), hampers the uptake and presentation of antigens by antigen-presenting cells (APCs) within the tumor itself. This limitation results in inadequate activation of immune responses against cancer. In contrast, immune cells in peritumoral tissue maintain their normal functions. In this context, we present an interesting approach to enhance cancer immunotherapy by utilizing engineered photosynthetic bacteria (PSB) and their outer membrane vesicles (OMVPSB) to capture and transport antigens to the outer regions of the tumor. We modified PSB with maleimide (PSB-MAL), which, when exposed to near-infrared (NIR) laser-mediated photothermal therapy (PTT), induced extensive cancer cell death and the release of tumor antigens. Subsequently, the NIR-phototactic PSB-MAL transported these tumor antigens to the peripheral regions of the tumor under NIR laser exposure. Even more intriguingly, PSB-MAL-derived OMVPSB-MAL effectively captured and delivered antigens to tumor-draining lymph nodes (TDLNs). This facilitated enhanced antigen presentation by mature and fully functional APCs in the TDLNs. This intricate communication network between PSB-MAL, the OMVPSB-MAL, and APCs promoted the efficient presentation of tumor antigens in the tumor periphery and TDLNs. Consequently, there was a notable increase in the infiltration of cytotoxic T lymphocytes (CTLs) into the tumor, triggering potent antitumor immune responses in both melanoma and breast cancer models. This cascade of events resulted in enhanced suppression of tumor metastasis and recurrence, underscoring the robust efficacy of our approach. Our interesting study, harnessing the potential of bacteria and OMVs to redirect tumor antigens for enhanced cancer immunotherapy, provides a promising path toward the development of personalized cancer vaccination strategies.

Catalytic Tunable Black Phosphorus/Ceria Nanozyme: A Versatile Oxidation Cycle Accelerator for Alleviating Cisplatin-Induced Acute Kidney Injury.

Oxidative stress is one leading inner cause of acute kidney injury (AKI) induced by cisplatin (DDP). Therefore, inhibiting oxidative stress is an important strategy to prevent the occurrence of DDP-induced AKI. Herein, a pH-selective "oxidative cycle accelerator" based on black phosphorus/ceria catalytic tunable nanozymes (BP@CeO2 -PEG) to effectively and persistently scavenge ROS for alleviating DDP-induced AKI is demonstrated. The BP@CeO2 -PEG nanozymes show pH-dependent multi-enzymatic activities, which are beneficial for selectively scavenging the excess ROS in renal tissues. In the neutral environment of kidneys, BP@CeO2 -PEG nanozymes can accelerate its catalytic "oxidative cycle" by increasing the ratio of Ce3+ /Ce4+ and improving the regeneration of ATP, effectively removing DDP-induced ROS. In addition, BP@CeO2 -PEG nanozymes can suppress the oxidative stress-triggered renal tubular epithelial cell apoptosis by inhibiting the PI3K/Akt signaling pathway. However, in the acidic environment of cancers, the presence of H+ inhibits the conversion of Ce4+ to Ce3+ , which in turn disrupts the oxidative cycle, resulting in the loss of ROS scavenging ability and ensuring the antitumor effect of DDP. Conclusively, the nanozymes offer an excellent antioxidant for alleviating cisplatin-induced AKI and extensive use in other ROS-based injuries.

MRI measurements of brain hippocampus volume in relation to mild cognitive impairment and Alzheimer disease: A systematic review and meta-analysis.

BACKGROUND: This is the first meta-analysis conducted to compare the hippocampal volume measured by magnetic resonance imaging (MRI) in healthy normal subjects, mild cognitive impairment (MCI) and Alzheimer disease (AD), and to analyze the relationship between hippocampal volume changes and MCI and AD. METHODS: English literatures published from January 2004 to December 2006 were extracted from PubMed, Embase, Wanfang Medical, and China National Knowledge Infrastructure databases. Statistical analysis was carried out with Stata/SE 16.0 software. RESULTS: The smaller the volume of the hippocampus measured by MRI, the more severe the cognitive impairment or AD. Different MRI post-measurement correction methods have different measurement results: Left hippocampal volume measured by MRI Raw volume method is negatively correlated with MCI and AD (OR [odds ratio] = 0.58, 95%CI [confidence interval]: 0.42, 0.75) right hippocampal volume measured was not associated with MCI OR AD (OR = 0.87, 95%CI: 0.56, 1.18); left hippocampal volume measured by MRI total intracranial volume (TIV) Correction was not associated with MCI and AD (OR = 0.90, 95%CI: 0.62, 1.19), measured right hippocampal volume was not associated with MCI OR AD (OR = 0.81, 95%CI: 0.49, 1.12); left hippocampal volume measured by MRI TIV Correction was not associated with MCI and AD (OR = 0.90, 95%CI: 0.62, 1.19), measured right hippocampus volume was negatively associated with MCI and AD (OR = 0.49, 95%CI: 0.35, 0.62). CONCLUSION: The shrinkage of hippocampus volume is closely related to MCI and AD. MRI measurement of hippocampus volume is not only an auxiliary diagnostic tool for MCI and AD, but also a good prognosis assessment tool.

[Application of self-made anti-pressure sore cotton cover in preventing facial pressure injury in patients with non-invasive ventilation].

OBJECTIVE: To observe the application effect of self-made anti-pressure sore cotton cover on the prevention of facial pressure injury in patients with non-invasive ventilation, and to explore the effective method of preventing facial pressure injury. METHODS: A prospective study was conducted. Patients with mild to moderate respiratory failure and non-invasive ventilation admitted to the department of intensive care medicine of Harisen International Peace Hospital Affiliated to Hebei Medical University from March 2020 to August 2021 were enrolled, and they were divided into gauze pad group, foam dressing group and self-made anti-pressure ulcer cotton cover group by random number table method. Before wearing the ventilator mask, the gauze pad group and the foam auxiliary dressing group should fold or cut out the auxiliary dressing with the corresponding size and suitable for the patient's facial contour. In the self-made anti-pressure sore cotton cover group, the ventilator cotton cover could be worn only by selecting the cotton cover suitable for the patient's face shape, aligning the vent to the mouth and nose, and tying the fixed belt behind the ear. The incidence of facial pressure sore, the time required to connect man-machine interface (from the preparation of auxiliary dressing for pressure sores to the connection of ventilator) and the cost of dressing were compared among the three groups. RESULTS: A total of 150 patients with non-invasive ventilation were enrolled, with 50 patients in each group. Compared with the gauze pad group and the foam dressing group, the incidence of facial pressure sore in the self-made anti-pressure sore cotton cover group was significantly reduced [6.0% (3/50) vs. 44.0% (22/50), 12.0% (6/50), both P < 0.05], and the time required to connect the man-machine interface was significantly shortened (minutes: 5.0±1.5 vs. 10.0±1.5, 8.0±2.0, both P < 0.05), dressing cost was significantly reduced (yuan: 30±10 vs. 150±20, 118±29, both P < 0.05). CONCLUSIONS: Compared with the gauze pad and the foam dressing, the incidence of facial pressure sore in non-invasive ventilation patients with self-made anti-pressure sore cotton cover is lower, the time required to connect man-machine interface is shorter, and the cost of pressure sore prevention dressing is less, which is suitable for the prevention of facial pressure injury in non-invasive ventilation patients.

A Fluorescent Probe for Investigating the Role of Biothiols in Signaling Pathways Associated with Cerebral Ischemia-Reperfusion Injury.

Cerebral ischemia-reperfusion injury (CIRI) is intimately associated with the redox regulation of biothiol, a crucial antioxidant marker that precludes the onset of ROS. We designed a novel fluorescent probe, DCI-Ac-Py, showing various physicochemical properties, such as high selectivity, exceptional signal-to-noise ratio, near-infrared (NIR) optical window, and blood-brain barrier (BBB) penetrability, for detecting biothiols in the brain. The picolinate serves as a specific recognition group that is rapidly activated by biothiol and undergoes nucleophilic substitution with the adjacent acrylic ester to yield the desired NIR probe. Additionally, the probe's lipid solubility is improved through the inclusion of halogen atoms, which aids in penetrating the BBB. Using DCI-Ac-Py, we investigated changes of biothiols in vivo in the brains of mice during CIRI. We found that biothiol-mediated NF-kB classical (P65-related) and nonclassical (RelB-related) pathways contribute to abundant ROS production induced by CIRI and that biothiols are involved in redox regulation. These findings provide new insights into the study of CIRI and shed light on the physiological and pathological mechanisms of biothiols in the brain.

A biodegradable hollow nanoagent enables a boosted chemodynamic therapy by simultaneous autophagy inhibition and macrophage reeducation.

Various therapeutic strategies, including chemotherapy, radiotherapy, photothermal therapy (PTT), and immunotherapy have been applied in cancer therapy. However, intrinsic or acquired therapeutic resistance is the main obstacle that attenuates the treatment effect of the therapeutic reagents used in these strategies. Studies have shown that autophagy and immunosuppressive tumor-associated macrophages (TAMs), as internal and external resistance mechanisms, would significantly compromise the effectiveness of cancer treatment. Therefore, selectively blocking the autophagy and repolarizing TAMs to anti-tumor phenotype (M1) will be effective for cancer treatments. Herein, an ambidextrous strategy that simultaneously inhibited autophagy and reeducated TAMs to promote anti-tumor therapy meditated by the iron-based nanocarriers was reported. The released Fe (II) ion reacted with the released artemisinin (ART) to produce ROS for chemodynamic therapy (CDT). The chloroquine (CQ) was used to inhibit autophagy in cancer cells and reset TAMs from the M2 phenotype to the M1 phenotype, eliminating the resistance of cancer cells and realizing an augmented therapeutic effect. This work provides a promising way for augmenting therapeutic efficiency by simultaneously interfering with two critical therapeutic resistance mechanisms.

Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.

OBJECTIVE: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. DESIGN: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. RESULTS: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. CONCLUSION: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.

Multi-walled carbon nanotubes reversing the bone formation of bone marrow stromal cells by activating M2 macrophage polarization.

Multi-walled carbon nanotubes (MWCNTs) are an excellent bone tissue repair material both in vitro and in vivo. The interactions between MWCNTs and single type of cells of bone tissue, including osteoblasts, bone marrow stromal cells (BMSCs) or osteoclasts, have been extensively studied. However, the interactions between MWCNTs with different types of cells in the bone microenvironment remain elusive. Bone microenvironment is a complex system composed of different types of cells, which have interactions between each other. In this work, the effects of MWCNTs on bone microenvironment were firstly studied by culture of MWCNTs with BMSCs, osteoblasts, osteoclasts, macrophages and vascular endothelial cells, respectively. Then, co-culture systems of macrophages-BMSCs, macrophages-calvaria and macrophages-BMSCs-vascular endothelial cells were treated with MWCNTs, respectively. The osteogenic differentiation of BMSCs and osteoblasts was inhibited when these two types of cells were cultured with MWCNTs, respectively. Strikingly, when co-culture MWCNTs with BMSCs and macrophages, the osteogenesis of BMSCs was promoted by inducing the M2 polymerization of macrophages. Meanwhile, MWCNTs promoted the bone formation in the osteolysis model of calvaria ex vivo. In addition, the formation of osteoclasts was inhibited, and angiogenesis was increased when treated with MWCNTs. This study revealed the inconsistent effects of MWCNTs on single type of bone cells and on the bone microenvironment. The results provided basic research data for the application of MWCNTs in bone tissue repair.

RNA-cleaving DNAzymes for accurate biosensing and gene therapy.

RNA-cleaving DNAzymes, which are single-stranded catalytic DNA, have attracted considerable attention in bioanalysis and biomedical applications because of their high stability, high catalytic activity, easy synthesis, easy functionalization, and modification. By incorporating these DNAzymes with amplification systems, the sensing platforms can be used to detect a series of targets with high sensitivity and selectivity. In addition, these DNAyzmes possess therapeutic potential by cutting the mRNA in cells and viruses to regulate the expression of the corresponding proteins. This review systematically summarizes the applications of RNA-cleaving DNAzymes in recent years, explaining the uniqueness and superiority of RNA-cleaving DNAzymes in biosensing and gene therapy. Finally, this review extends the discussion to the challenges and perspectives of applying RNA-cleaving DNAzyme as a diagnostic and therapeutic agent. This review provides the researchers with valuable suggestions and promotes the development of DNAzymes for accurate analysis, early diagnosis, and effective therapy in medicine and their broader applications beyond biomedicine.

Effect of Annular Laser Metal Deposition (ALMD) Process Parameters on Track Geometry and Thermal History on Ti6Al4V Alloy Clad.

Annular laser metal deposition (ALMD) is a rising technology that fabricates near-net-shaped components. In this research, a single factor experiment with 18 groups was designed to study the influence of process parameters on the geometric characteristics (bead width, bead height, fusion depth, and fusion line) and thermal history of Ti6Al4V tracks. The results show that discontinuous and uneven tracks with pores or large-sized incomplete fusion defects were observed when the laser power was less than 800 W or the defocus distance was -5 mm. The laser power had a positive effect on the bead width and height, while the scanning speed had the opposite effect. The shape of the fusion line varied at different defocus distances, and the straight fusion line could be obtained with the appropriate process parameters. The scanning speed was the parameter that had the greatest effect on the molten pool lifetime and solidification time as well as the cooling rate. In addition, the microstructure and microhardness of the thin wall sample were also studied. Many clusters with various sizes in different zones were distributed within the crystal. The microhardness ranged from 330 HV to 370 HV.

Bionic lipoprotein loaded with chloroquine-mediated blocking immune escape improves antitumor immunotherapy.

Tumor immunotherapy hold great promise for eradicating tumors. However, immune escape and the immunosuppressive microenvironment of tumor usually limit the efficiency of tumor immunotherapy. Therefore, simultaneously blocking immune escape and improving immunosuppressive microenvironment are the current problems to be solved urgently. Among them, CD47 on cancer cells membrane could bind to signal regulatory protein α (SIRPα) on macrophages membrane and sent out "don't eat me" signal, which was an important pathway of immune escape. The large number of M2-type macrophages in tumor microenvironment was a significant factor contributing to the immunosuppressive microenvironment. Here, we present a drug loading system for enhancing cancer immunotherapy, comprising CD47 antibody (aCD47) and chloroquine (CQ) with bionic lipoprotein (BLP) carrier (BLP-CQ-aCD47). On the one hand, as drug delivery carrier, BLP could allow CQ to be preferentially taken up by M2-type macrophages, thereby efficiently polarized M2-type tumor-promoting cells into M1-type anti-tumor cells. On the other hand, blocking CD47 from binding to SIRPα could block the "don't eat me" signal, and improve the phagocytosis of macrophages to tumor cells. Taken together, BLP-CQ-aCD47 could block immune escape, improve immunosuppressive microenvironment of tumor, and induce a strong immune response without substantial systemic toxicity. Therefore, it provides a new idea for tumor immunotherapy.

Submesoscale inverse energy cascade enhances Southern Ocean eddy heat transport.

Oceanic eddy-induced meridional heat transport (EHT) is an important process in the Southern Ocean heat budget, the variability of which significantly modulates global meridional overturning circulation (MOC) and Antarctic sea-ice extent. Although it is recognized that mesoscale eddies with scales of ~40-300 km greatly contribute to the EHT, the role of submesoscale eddies with scales of ~1-40 km remains unclear. Here, using two state-of-the-art high-resolution simulations (resolutions of 1/48° and 1/24°), we find that submesoscale eddies significantly enhance the total poleward EHT in the Southern Ocean with an enhancement percentage reaching 19-48% in the Antarctic Circumpolar Current band. By comparing the eddy energy budgets between the two simulations, we detect that the primary role of submesoscale eddies is to strengthen mesoscale eddies (and thus their heat transport capability) through inverse energy cascade rather than directly through submesoscale heat fluxes. Due to the submesoscale-mediated enhancement of mesoscale eddies in the 1/48° simulation, the clockwise upper cell and anti-clockwise lower cell of the residual-mean MOC in the Southern Ocean are weakened and strengthened, respectively. This finding identifies a potential route to improve the mesoscale parameterization in climate models for more accurate simulations of the MOC and sea ice variability in the Southern Ocean.

Separable Microneedles with Photosynthesis-Driven Oxygen Manufactory for Diabetic Wound Healing.

Oxygen plays an important role in diabetic chronic wound healing by regulating various life activities such as cell proliferation, migration, and angiogenesis. Therefore, oxygen-delivering systems have drawn much attention and evolved continuously. Here, we propose that an active Chlorella vulgaris (Cv)-loaded separable microneedle (MN) can be used to control oxygen delivery, which then promotes wound healing. The Cv-loaded microneedles (CvMN) consist of a polyvinyl acetate (PVA) substrate and gelatin methacryloyl (GelMA) tips with encapsulated Cv. Once CvMN is applied to diabetic wound, the PVA basal layer is rapidly dissolved in a short time, while the noncytotoxic and biocompatible GelMA tips remain in the skin. By taking advantage of the photosynthesis of Cv, oxygen would be continuously produced in a green way and released from CvMN in a controlled manner. Both in vitro and in vivo results showed that CvMN could promote cell proliferation, migration, and angiogenesis and enhance wound healing in diabetic mice effectively. The remarkable therapeutic effect is mainly attributed to the continuous generation of dissolved oxygen in CvMN and the presence of antioxidant vitamins, γ-linolenic acid, and linoleic acid in Cv. Thus, CvMN provides a promising strategy for diabetic wound healing with more possibility of clinical transformations.