Narrow Bandgap Schottky Heterojunction Sonosensitizer with High Electron-Hole Separation Boosted Sonodynamic Therapy in Bladder Cancer.

Sonodynamic therapy (SDT) is applied to bladder cancer (BC) given its advantages of high depth of tissue penetration and nontoxicity due to the unique anatomical location of the bladder near the abdominal surface. However, low electron-hole separation efficiency and wide bandgap of sonosensitizers limit the effectiveness of SDT. This study aims to develop a TiO2-Ru-PEG Schottky heterojunction sonosensitizer with high electron-hole separation and narrow bandgap for SDT in BC. Density functional theory (DFT) calculations and experiments collectively demonstrate that the bandgap of TiO2-Ru-PEG is reduced due to the Schottky heterojunction with the characteristic of crystalline-amorphous interface formed by the deposition of ruthenium (Ru) within the shell layer of TiO2. Thanks to the enhancement of oxygen adsorption and the efficient separation of electron-hole pairs, TiO2-Ru-PEG promotes the generation of reactive oxygen species (ROS) under ultrasound (US) irradiation, resulting in cell cycle arrest and apoptosis of bladder tumor cells. The in vivo results prove that TiO2-Ru-PEG boosted the subcutaneous and orthotopic bladder tumor models while exhibiting good safety. This study adopts the ruthenium complex for optimizing sonosensitizers, contributing to the progress of SDT improvement strategies and presenting a paradigm for BC therapy.

Cobalt Single-Atom Reverse Hydrogen Spillover for Efficient Electrochemical Water Dissociation and Dechlorination.

Efficient water dissociation to atomic hydrogen (H*) with restrained recombination of H* is crucial for improving the H* utilization for electrochemical dechlorination, but is currently limited by the lack of feasible electrodes. Herein, we developed a monolithic single-atom electrode with Co single atoms anchored on the inherent oxide layer of titanium foam (Co1-TiOx/Ti), which can efficiently dissociate water into H* and simultaneously inhibit the recombination of H*, by taking advantage of the single-atom reverse hydrogen spillover effect. Experimental and theoretical calculations demonstrated that H* could be rapidly generated on the oxide layer of titanium foam, and then overflowed to the adjacent Co single atom for the reductive dechlorination. Using chloramphenicol as a proof-of-concept verification, the resulting Co1-TiOx/Ti monolithic electrode exhibited an unprecedented performance with almost 100 % dechlorination at -1.0 V, far superior to that of traditional indirect reduction-driven commercial Pd/C (52 %) and direct reduction-driven Co1-N-C (44 %). Moreover, its dechlorination rate constant of 1.64 h-1 was 4.3 and 8.6 times more active than those of Pd/C (0.38 h-1) and Co1-N-C (0.19 h-1), respectively. Our research sheds light on the rational design of hydrogen spillover-related electrocatalysts to simultaneously improve the H* generation, transfer, and utilization for environmental and energy applications.

Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreatic ß-cell Dysfunction.

OBJECTIVE: While the reduction of transient receptor potential channel subfamily M member 5 (TRPM5) has been reported in islet cells from type 2 diabetic (T2D) mouse models, its role in lipotoxicity-induced pancreatic ß-cell dysfunction remains unclear. This study aims to study its role. METHODS: Pancreas slices were prepared from mice subjected to a high-fat-diet (HFD) at different time points, and TRPM5 expression in the pancreatic ß cells was examined using immunofluorescence staining. Glucose-stimulated insulin secretion (GSIS) defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate (Palm). Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm, and the TRPM5 expression was detected using qRT-PCR and Western blotting. Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown. The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5 (Ad-Trpm5). RESULTS: HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets. Palm reduced TRPM5 protein expression in a time- and dose-dependent manner in MIN6 cells. Palm also inhibited TRPM5 expression in primary mouse islets. Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis. Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique to ß cells. CONCLUSION: Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreatic ß cells both in vivo and in vitro and, in turn, drives ß-cell dysfunction.

Sex differences in the relationships between macronutrients and all-cause mortality in individuals with metabolically unhealthy overweight/obesity.

This study investigates sex differences in the effects of macronutrient quantity, quality, and timing on mortality in metabolically unhealthy overweight/obesity (MUO) populations. The study included 18,345 participants, including 9204 men and 9141 women. The Cox proportional risk model and isocaloric substitution effects were used to examine the association of macronutrient intake and subtype with all-cause mortality in the MUO populations. After adjusting for the potential covariates, The risk of all-cause mortality was elevated in men in the highest 25% percentile of poor-quality carbohydrates compared with men in the lowest quartile (odds ratio [OR]: 2.04; 95% confidence interval [CI], 1.40-2.98). Compared with women in the lowest quartile, the risk of all-cause mortality for women in the highest 25% percentile for high-quality carbohydrates (OR: 0.74; 95% CI, 0.55-0.99) and unsaturated fatty acids (OR: 0.54; 95% CI, 0.32-0.93) were decreased. In women, replacing low-quality carbohydrates with high-quality carbohydrates on an isocaloric basis reduces the risk of all-cause mortality by approximately 9%. We find that different macronutrient consumption subtypes are associated with all-cause mortality in MUO populations, with differential effects between men and women, and that the risk of all-cause mortality is influenced by macronutrient quality and meal timing.

Engineering the Coordination Environment of Ir Single Atoms with Surface Titanium Oxide Amorphization for Superior Chlorine Evolution Reaction.

The chlorine evolution reaction (CER) is essential for industrial Cl2 production but strongly relies on the use of dimensionally stable anode (DSA) with high-amount precious Ru/Ir oxide on a Ti substrate. For the purpose of sustainable development, precious metal decrement and performance improvement are highly desirable for the development of CER anodes. Herein, we demonstrate that surface titanium oxide amorphization is crucial to regulate the coordination environment of stabilized Ir single atoms for efficient and durable chlorine evolution of Ti monolithic anodes. Experimental and theoretical results revealed the formation of four-coordinated Ir1O4 and six-coordinated Ir1O6 sites on amorphous and crystalline titanium oxides, respectively. Interestingly, the Ir1O4 sites exhibited a superior CER performance, with a mass activity about 10 and 500 times those of the Ir1O6 counterpart and DSA, respectively. Moreover, the Ir1O4 anode displayed excellent durability for 200 h, far longer than that of its Ir1O6 counterpart (2 h). Mechanism studies showed that the unsaturated Ir in Ir1O4 was the active center for chlorine evolution, which was changed to the top-coordinated O in Ir1O6. This change of active sites greatly affected the adsorption energy of Cl species, thus accounting for their different CER activity. More importantly, the amorphous structure and restrained water dissociation of Ir1O4 synergistically prevent oxygen permeation across the Ti substrate, contributing to its long-term CER stability. This study sheds light on the importance of single-atom coordination structures in the reactivity of catalysts and offers a facile strategy to prepare highly active single-atom CER anodes via surface titanium oxide amorphization.

Association between inflammatory biomarkers and mortality in individuals with type 2 diabetes: NHANES 2005-2018.

PURPOSE: This study aimed to examine independent association between inflammatory biomarkers and all-cause mortality as well as cardio-cerebrovascular disease (CCD) mortality among U.S. adults with diabetes. METHODS: A cohort of 6412 U.S. adults aged 20 or older was followed from the start until December 31, 2019. Statistical models such as Cox proportional hazards model (Cox) and Kaplan-Meier (K-M) survival curves were employed to investigate the associations between the inflammatory biomarkers and all-cause mortality and CCD mortality. RESULTS: After adjusting for confounding factors, the highest quartile of inflammatory biomarkers (NLR HR = 1.99; 95 % CI:1.54-2.57, MLR HR = 1.93; 95 % CI:1.46-2.54, SII HR = 1.49; 95 % CI:1.18-1.87, SIRI HR = 2.32; 95 % CI:1.81-2.96, nLPR HR = 2.05; 95 % CI:1.61-2.60, dNLR HR = 1.94; 95 % CI:1.51-2.49, AISI HR = 1.73; 95 % CI:1.4 1-2.12)) were positively associated with all-cause mortality compared to those in the lowest quartile. K-M survival curves indicated that participants with an inflammatory biomarker above a certain threshold had a higher risk of both all-cause mortality and CCD mortality (Log rank P < 0.05). CONCLUSION: Some biomarkers such as NLR, MLR, SII, AISI, SIRI, and dNLR, are significantly associated with all-cause mortality and CCD mortality among U.S. adults with diabetes. The risk of both outcomes increased when the biomarkers surpassed a specific threshold.

Flexible Polyolefin Elastomer/Paraffin Wax/Alumina/Graphene Nanoplatelets Phase Change Materials with Enhanced Thermal Conductivity and Mechanical Performance for Solar Conversion and Thermal Energy Storage Applications.

In this study, electrically insulating polyolefin elastomer (POE)-based phase change materials (PCMs) comprising alumina (Al2O3) and graphene nanoplatelets (GNPs) are prepared using a conventional injection moulding technique, which exhibits promising applications for solar energy storage due to the reduced interfacial thermal resistance, excellent stability, and proficient photo-thermal conversion efficiency. A synergistic interplay between Al2O3 and GNPs is observed, which facilitates the establishment of thermally conductive pathways within the POE/paraffin wax (POE/PW) matrix. The in-plane thermal conductivity of POE/PW/GNPs 5 wt%/Al2O3 40 wt% composite reaches as high as 1.82 W m-1K-1, marking a remarkable increase of ≈269.5% when compared with that of its unfilled POE/PW counterpart. The composite exhibits exceptional heat dissipation capabilities, which is critical for thermal management applications in electronics. Moreover, POE/PW/GNPs/Al2O3 composites demonstrate outstanding electrical insulation, enhanced mechanical performance, and efficient solar energy conversion and transportation. Under 80 mW cm-2 NIR light irradiation, the temperature of the POE/PW/GNPs 5 wt%/Al2O3 40 wt% composite reaches approximately 65 °C, a notable 20 °C improvement when compared with the POE/PW blend. The pragmatic and uncomplicated preparation method, coupled with the stellar performance of the composites, opens a promising avenue and broader possibility for developing flexible PCMs for solar conversion and thermal storage applications.

Self-Adjuvanting Polyguanidine Nanovaccines for Cancer Immunotherapy.

Tapping into the innate immune system's power, nanovaccines can induce tumor-specific immune responses, which is a promising strategy in cancer immunotherapy. However, traditional vaccine design, requiring simultaneous loading of antigens and adjuvants, is complex and poses challenges for mass production. Here, we developed a tumor nanovaccine platform that integrates adjuvant functions into the delivery vehicle, using branched polyguanidine (PolyGu) nanovaccines. These nanovaccines were produced by modifying polyethylenimine (PEI) with various guanidine groups, transforming PEI's cytotoxicity into innate immune activation. The PolyGu nanovaccines based on poly(phenyl biguanidine ) (Poly-PBG) effectively stimulated dendritic cells, promoted their maturation via the TLR4 and NLRP3 pathways, and displayed robust in vivo immune activity. They significantly inhibited tumor growth and extended mouse survival. The PolyGu also showed promise for constructing more potent mRNA-based nanovaccines, offering a platform for personalized cancer vaccine. This work advances cancer immunotherapy toward potential clinical application by introducing a paradigm for developing self-adjuvanting nanovaccines.

Spin polarized Fe1-Ti pairs for highly efficient electroreduction nitrate to ammonia.

Electrochemical nitrate reduction to ammonia offers an attractive solution to environmental sustainability and clean energy production but suffers from the sluggish *NO hydrogenation with the spin-state transitions. Herein, we report that the manipulation of oxygen vacancies can contrive spin-polarized Fe1-Ti pairs on monolithic titanium electrode that exhibits an attractive NH3 yield rate of 272,000 µg h-1 mgFe-1 and a high NH3 Faradic efficiency of 95.2% at -0.4 V vs. RHE, far superior to the counterpart with spin-depressed Fe1-Ti pairs (51000 µg h-1 mgFe-1) and the mostly reported electrocatalysts. The unpaired spin electrons of Fe and Ti atoms can effectively interact with the key intermediates, facilitating the *NO hydrogenation. Coupling a flow-through electrolyzer with a membrane-based NH3 recovery unit, the simultaneous nitrate reduction and NH3 recovery was realized. This work offers a pioneering strategy for manipulating spin polarization of electrocatalysts within pair sites for nitrate wastewater treatment.

Small EV-based delivery of CpG ODNs for melanoma postsurgical immunotherapy.

Blocking programmed cell death protein 1 (PD-1) is an effective therapeutic strategy for melanoma. However, patients often develop tumor recurrence postoperatively due to the low response rate to the anti-PD-1 antibody (aPD-1). In this study, we developed an in situ sprayable fibrin gel that contains cytosine-guanine oligodeoxynucleotides (CpG ODNs)-modified ovalbumin (OVA) antigen-expressing bone marrow dendritic cell (DC)-derived small extracellular vesicles (DC-sEVs) and aPD-1. CpG ODNs can activate DCs, which have potent immunostimulatory effects, by stimulating both the maturation and activation of tumor-infiltrating dendritic cells (TIDCs) and DCs in tumor-draining lymph nodes (TDLNs). In addition, DC-sEVs can deliver OVA to the same DCs, leading to the specific expression of tumor antigens by antigen-presenting cells (APCs). In brief, the unique synergistic combination of aPD-1 and colocalized delivery of immune adjuvants and tumor antigens enhances antitumor T-cell immunity, not only in the tumor microenvironment (TME) but also in TDLNs. This effectively attenuates local tumor recurrence and metastasis. Our results suggest that dual activation by CpG ODNs prolongs the survival of mice and decreases the recurrence rate in an incomplete tumor resection model, providing a promising approach to prevent B16-F10-OVA melanoma tumor recurrence and metastasis.

Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy.

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.

Decoupling of the Confused Complex in Oxidation of 3,3',5,5'-Tetramethylbenzidine for the Reliable Chromogenic Bioassay.

Regulation of the reaction pathways is a perennial theme in the field of chemistry. As a typical chromogenic substrate, 3,3',5,5'-tetramethylbenzidine (TMB) generally undertakes one-electron oxidation, but the product (TMBox1) is essentially a confused complex and is unstable, which significantly hampers the clinic chromogenic bioassays for more than 50 years. Herein, we report that sodium dodecyl sulfate (SDS)-based micelles could drive the direct two-electron oxidation of TMB to the final stable TMBox2. Rather than activation of H2O2 oxidant in the one-electron TMB oxidation by common natural peroxidase, activation of the TMB substrate by SDS micelles decoupled the thermodynamically favorable complex between TMBox2 with unreacted TMB, leading to an unusual direct two-electron oxidation pathway. Mechanism studies demonstrated that the complementary spatial and electrostatic isolation effects, caused by the confined hydrophobic cavities and negatively charged outer surfaces of SDS micelles, were crucial. Further cascading with glucose oxidase, as a proof-of-concept application, allowed glucose to be more reliably measured, even in a broader range of concentrations without any conventional strong acid termination.

Compact engineered human mechanosensitive transactivation modules enable potent and versatile synthetic transcriptional control.

Engineered transactivation domains (TADs) combined with programmable DNA binding platforms have revolutionized synthetic transcriptional control. Despite recent progress in programmable CRISPR-Cas-based transactivation (CRISPRa) technologies, the TADs used in these systems often contain poorly tolerated elements and/or are prohibitively large for many applications. Here, we defined and optimized minimal TADs built from human mechanosensitive transcription factors. We used these components to construct potent and compact multipartite transactivation modules (MSN, NMS and eN3x9) and to build the CRISPR-dCas9 recruited enhanced activation module (CRISPR-DREAM) platform. We found that CRISPR-DREAM was specific and robust across mammalian cell types, and efficiently stimulated transcription from diverse regulatory loci. We also showed that MSN and NMS were portable across Type I, II and V CRISPR systems, transcription activator-like effectors and zinc finger proteins. Further, as proofs of concept, we used dCas9-NMS to efficiently reprogram human fibroblasts into induced pluripotent stem cells and demonstrated that mechanosensitive transcription factor TADs are efficacious and well tolerated in therapeutically important primary human cell types. Finally, we leveraged the compact and potent features of these engineered TADs to build dual and all-in-one CRISPRa AAV systems. Altogether, these compact human TADs, fusion modules and delivery architectures should be valuable for synthetic transcriptional control in biomedical applications.

Tg(Δ113p53:cmyc) Transgene Upregulates glut1 Expression to Promote Zebrafish Heart Regeneration.

The heart switches its main metabolic substrate from glucose to fatty acids shortly after birth, which is one of reasons for the loss of heart regeneration capability in adult mammals. On the contrary, metabolic shifts from oxidative phosphorylation to glucose metabolism promote cardiomyocyte (CM) proliferation after heart injury. However, how glucose transportation in CMs is regulated during heart regeneration is still not fully understood. In this report, we found that the expression of Glut1 (slc2a1) was upregulated around the injury site of zebrafish heart, accompanied by an increase in glucose uptake at the injury area. Knockout of slc2a1a impaired zebrafish heart regeneration. Our previous study has demonstrated that the expression of Δ113p53 is activated after heart injury and Δ113p53+ CMs undergo proliferation to contribute to zebrafish heart regeneration. Next, we used the Δ113p53 promoter to generate the Tg(Δ113p53:cmyc) zebrafish transgenic line. Conditional overexpression of cmyc not only significantly promoted zebrafish CM proliferation and heart regeneration but also significantly enhanced glut1 expression at the injury site. Inhibiting Glut1 diminished the increase in CM proliferation in Tg(Δ113p53:cmyc) injured hearts of zebrafish. Therefore, our results suggest that the activation of cmyc promotes heart regeneration through upregulating the expression of glut1 to speed up glucose transportation.

Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.

BRSK2 in pancreatic ß cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and ß-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in ß cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible ß-cell-specific Brsk2 knockout (ßKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, ßKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature ß cells reversibly triggers hyperglycemia due to ß-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and ß-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in ß cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between ß cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation.

The immunologically "cold" microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

Insight into Iron Leaching from an Ascorbate-Oxidase-like Fe-N-C Nanozyme and Oxygen Reduction Selectivity.

Ascorbate (H2 A) is a well-known antioxidant to protect cellular components from free radical damage and has also emerged as a pro-oxidant in cancer therapies. However, such "contradictory" mechanisms underlying H2 A oxidation are not well understood. Herein, we report Fe leaching during catalytic H2 A oxidation using an Fe-N-C nanozyme as a ferritin mimic and its influence on the selectivity of the oxygen reduction reaction (ORR). Owing to the heterogeneity, the Fe-Nx sites in Fe-N-C primarily catalyzed H2 A oxidation and 4 e- ORR via an iron-oxo intermediate. Nonetheless, trace O2 ⋅- produced by marginal N-C sites through 2 e- ORR accumulated and attacked Fe-Nx sites, leading to the linear leakage of unstable Fe ions up to 420 ppb when the H2 A concentration increased to 2 mM. As a result, a substantial fraction (ca. 40 %) of the N-C sites on Fe-N-C were activated, and a new 2+2 e- ORR path was finally enabled, along with Fenton-type H2 A oxidation. Consequently, after Fe ions diffused into the bulk solution, the ORR at the N-C sites stopped at H2 O2 production, which was the origin of the pro-oxidant effect of H2 A.

In Situ Sprayed Nanovaccine Suppressing Exosomal PD-L1 by Golgi Apparatus Disorganization for Postsurgical Melanoma Immunotherapy.

The anti-PD-L1 immunotherapy has shown promise in treating cancer. However, certain patients with metastatic cancer have low response and high relapse rates. A main reason is systemic immunosuppression caused by exosomal PD-L1, which can circulate in the body and inhibit T cell functions. Here, we show that Golgi apparatus-Pd-l1-/- exosome hybrid membrane coated nanoparticles (GENPs) can significantly reduce the secretion of PD-L1. The GENPs can accumulate in tumors through homotypic targeting and effectively deliver retinoic acid, inducing disorganization of the Golgi apparatus and a sequence of intracellular events including alteration of endoplasmic reticulum (ER)-to-Golgi trafficking and subsequent ER stress, which finally disrupts the PD-L1 production and the release of exosomes. Furthermore, GENPs could mimic exosomes to access draining lymph nodes. The membrane antigen of PD-l1-/- exosome on GENPs can activate T cells through a vaccine-like effect, strongly promoting systemic immune responses. By combining GENPs with anti-PD-L1 treatment in the sprayable in situ hydrogel, we have successfully realized a low recurrence rate and substantially extended survival periods in mice models with incomplete metastatic melanoma resection.

Alginate-modulated continuous assembly of iron/tannic acid composites as photothermally responsive wound dressings for hemostasis and drug resistant bacteria eradication.

Multifunctional dressing materials are highly required to combat multidrug resistant bacteria in wound infections. Here an alginate-based aerogel dressing is reported that combines photothermal bactericidal activity, hemostatic property, and free radical scavenging for skin wound disinfection and accelerated wound healing. The aerogel dressing is facilely constructed by immersing a clean nail (Fe) in a mixed solution of sodium alginate (Alg) and tannic acid (TA), followed by freezing, solvent replacement, and air drying. The Alg matrix plays an essential role in modulating the continuous assembly process between TA and Fe to allow the homogenous distribution of TA-Fe metal-phenolic networks (MPN) in the resulting composite, without forming aggregates. The photothermally responsive Nail-TA/Alg aerogel dressing is successfully applied in a murine skin wound model infected with Methicillin-resistant Staphylococcus aureus (MRSA). This work provides a facile strategy to integrate MPN with the hydrogel/aerogel matrix through in situ chemistry, which is promising for developing multifunctional biomaterials and biomedicine.