A Metal Chelation Therapy to Effectively Eliminate Breast Cancer and Intratumor Bacteria While Suppressing Tumor Metastasis by Copper Depletion and Zinc Ions Surge.

The intratumor microbiota results in the immunosuppressive microenvironment and facilitates tumor growth and metastasis. However, developing a synergistic therapy with antitumor, antibacterial, and antimetastatic effects faces enormous challenges. Here, we propose an metal chelation therapy to effectively eliminate tumor and intratumor bacteria and suppress tumor metastasis. Different from traditional chelation therapy that only consumes metal elements, this therapy not only eliminates the crucial metal elements for tumor metabolism but also releases new metal ions with antitumor and antibacterial properties. Based on the high demand for copper in breast cancer, we prepare a fibrous therapeutic nanoagent (Zn-PEN) by chelating D-Penicillamine (D-PEN) with Zn2+. Firstly, Zn-PEN achieves dual inhibition of oxidative phosphorylation and glycolysis metabolism  through copper depletion and Zn2+ activated cGAS-STING pathway, thus inducing tumor cell death. Secondly, Zn-PEN has the capability to eradicate Fusobacterium nucleatum in breast cancer, thereby mitigating its immunosuppressive impact on the tumor microenvironment. Finally, Zn-PEN effectively inhibits tumor metastasis through multiple routes, including the inhibition of epithelial-mesenchymal transition process, activation of cGAS-STING pathway, and elimination with F. nucleatum. Therefore, we verify the feasibility of Zn-PEN mediated metal chelation therapy in a 4T1 model infected with F. nucleatum, providing a new therapeutic strategy for inhibiting tumor metastasis.

Zingerone attenuates concanavalin A-induced acute liver injury by restricting inflammatory responses.

Autoimmune hepatitis (AIH), an immune-mediated liver injury, plays an important role in the development and pathogenesis of several liver diseases. However, therapeutic alternatives for the treatment of AIH remain limited. Zingerone (ZIN) is a natural non-toxic phenolic compound extracted from ginger that possesses various pharmacological activities. Thus, this study aimed to investigate the effect of ZIN on AIH using a mouse model of acute liver injury induced by concanavalin A (Con A). To establish liver injury, C57BL/6J mice were intraperitoneally administered ZIN, followed by 20 mg/kg Con A after 3 h. Thereafter, the liver and serum were collected for analysis. The results revealed that ZIN pretreatment significantly suppressed the elevation of liver injury markers induced by Con A exposure and improved the survival of mice. Additionally, ZIN significantly ameliorated liver histopathological injury, hepatocyte apoptosis, and oxidative stress. Notably, ZIN inhibited hepatic M1 macrophage polarization and decreased the expression of M1 macrophage-associated pro-inflammatory genes and cytokines, including interleukin-1ß (IL-1ß), IL-12, IL-6, and tumor necrosis factor-α (TNF-α). Western blotting analysis indicated that ZIN inhibited the phosphorylation of extracellular receptor kin, c-Jun N-terminal kinase, and p65 in vitro. Taken together, these results suggest that ZIN exerts a protective effect in the Con A-induced acute liver injury model by inhibiting M1 macrophage polarization and suppressing NF-κB, mitogen-activated protein kinase, and interferon regulatory factor signaling pathways. This highlights the possibility of using ZIN as a safe drug for the treatment of liver injury and provides a novel therapeutic direction for clinical studies on liver diseases.

Multifunctional Copper-Phenolic Nanopills Achieve Comprehensive Polyamines Depletion to Provoke Enhanced Pyroptosis and Cuproptosis for Cancer Immunotherapy.

The overexpression of polyamines in tumor cells contributes to the establishment of immunosuppressive microenvironment and facilitates tumor growth. Here, it have ingeniously designed multifunctional copper-piceatannol/HA nanopills (Cu-Pic/HA NPs) that effectively cause total intracellular polyamines depletion by inhibiting polyamines synthesis, depleting intracellular polyamines, and impairing polyamines uptake, resulting in enhanced pyroptosis and cuproptosis, thus activating a powerful immune response to achieve anti-tumor therapy. Mitochondrial dysfunction resulting from overall intracellular polyamines depletion not only leads to the surge of copper ions in mitochondria, thereby causing the aggregation of toxic proteins to induce cuproptosis, but also triggers the accumulation of reactive oxygen species (ROS) within mitochondria, which further upregulates the expression of zDHHC5 and zDHHC9 to promote the palmitoylation of gasdermin D (GSDMD) and GSDMD-N, ultimately inducing enhanced pyroptosis. Then the occurrence of enhanced pyroptosis and cuproptosis is conductive to remodel the immunosuppressive tumor microenvironment, thus activating anti-tumor immune responses and ultimately effectively inhibiting tumor growth and metastasis. This therapeutic strategy of enhanced pyroptosis and cuproptosis through comprehensive polyamines depletion provides a novel template for cancer immunotherapy.

Propylene glycol alginate sodium sulfate suppressed lung metastasis by blocking P-selectin to recruit CD4 regulatory T cells.

P-selectin has been shown to enhance growth and metastasis of mouse tumors by promoting regulatory T cell (Treg) infiltration into the tumors. Theoretically, a P-selectin antagonist could suppress the process. Popylene glycol alginate sodium sulfate (PSS) is a heparin-like marine drug, which was originally approved to treat cardiovascular disease in China. Previously, we reported that PSS was an effective P-selectin antagonist in vitro. However, it is unknown whether PSS can regulate Treg infiltration and its effect on lung metastasis in vivo. Our results showed that PSS at 30 mg/kg significantly suppressed lung metastasis and improved overall survival, with potency comparable to the positive control LMWH. Mechanistic study indicated that PSS blocked tumor cells adhesion and activated platelets by directly binding with activated platelet's P-selectin. Compared to the model group, PSS decreased the percent of Tregs by 63 % in lungs after treating for 21 days while increasing CD8+ T cells (1.59-fold) and Granzyme B+ CD8 T cells (2.08-fold)' percentage for generating an adaptive response for systemic tumor suppression. The study indicated that the P-selectin antagonist, PSS, suppressed lung metastasis by inhibiting the infiltration of regulatory T cells (Treg) into the tumors.

MiR-93-5p inhibits ovarian cancer through SLC7A11-mediated-ferroptosis.

Aim: Ovarian cancer (OC) is the most lethal gynecological malignancy, which seriously affects the prognosis and life quality of female patients. Therefore, new therapeutic targets and treatments are urgently needed. Methods: Expression levels of miR-93-5p and SLC7A11 and ferroptosis status in paracancerous and tumor tissues were examined and compared. The effect of the miR-93-5p-SLC7A11 regulatory loop on the malignant phenotype as well as the ferroptosis phenotype of SKOV3 cells was assessed. Furthermore, the interaction between miR-93-5p and SLC7A11 was confirmed via rescue experiment. Results: In this study, we found that miR-93-5p was lowly expressed in cancer tissues, and suggested that overexpression of miR-93-5p could target SLC7A11 to reduce its expression and promote ferroptosis, thereby inhibiting the malignant biological behaviors such as proliferation, invasion and migration, while knockdown of miR-93-5p restrained ferroptosis and promoting tumor growth. Besides, erastin, as a specific inhibitor of SLC7A11, could target down the expression of SLC7A11, induce the occurrence of ferroptosis, and reverse the effect of knockdown of miR-93-5p. Conclusions: Taken together, our findings disclosed that miR-93-5p increased the level of ferroptosis and inhibited the progression of OC by targeting and inhibiting the expression level of SLC7A11, which was a potential treatment in OC.

Improving physical stability of microalgae protein-based emulsions under acidic and neutral conditions via carboxymethyl chitosan complexation.

The emulsification stability of microalgae protein (MP) is limited to strongly alkaline conditions, restricting its applications in food processing. This study aims to investigate the capability of carboxymethyl chitosan (CMCS) to improve MP's emulsification stability over a wider pH range. Results indicated soluble MP-CMCS complexes formed at pH 2, 4, and 7, while aggregation of the complexes occurred at pH 8. The complexes stabilized emulsions exhibited smaller droplet sizes and higher absolute zeta potential at pH 2, 4, and 7 compared to pH 8. After 2 weeks of storage, emulsions remained stable at pH 2, 4, and 7, with significant delamination at pH 8. Laser confocal microscopy confirmed uniform droplet distribution at pH 2 and 7, with slight fusion at pH 4. The complexes stabilized emulsions exhibited higher viscosity and shear stress than MP stabilized emulsions at pH 2, 4, and 7. The stronger viscoelastic properties and higher storage moduli (G') values of MP-CMCS complexes under acidic and neutral conditions indicated stronger intermolecular interactions compared to alkaline conditions. The increase in G' and loss moduli (G") values for emulsions at pH 8 under stress highlighted the significant impact on network structure strength and viscosity in these emulsions. This study elucidated the binding interactions between MP and CMCS under various pH conditions, and demonstrated a feasible approach to improving MP's emulsification stability over a wider pH range.

Effect of Interval Between Neoadjuvant Chemotherapy and Surgery on Oncological Outcomes in Poor Responders With Locally Advanced Breast Cancer.

PURPOSE: The interval between neoadjuvant chemotherapy (NAC) and surgery for locally advanced breast cancer (LABC) remains controversial. At the same time, the prognostic effect of delayed surgery in patients with poor responses is currently unclear. METHODS: Data was collected from patients who had poor responses to NAC and underwent modified radical surgery from January 2013 to December 2018. The interval from completion of NAC to surgery was divided into two groups: a longer (greater than four weeks) or shorter (four weeks or less) interval. The associations of these interval groups with overall survival (OS) and recurrence-free survival (RFS) were evaluated by multivariable Cox models adjusting for the existing prognostic factors. Propensity score matching (PSM) was used to minimize election bias. RESULTS: A total of 1,229 patients (mean age, 47.2 ± 8.9 years; median follow-up duration, 32.67 [6.57-52.63] months) were included. The 5-year OS rates were 73.2% and 60.8% in the shorter (n = 171) and longer interval group (n = 1,058), respectively, while the 3-year RFS rates were 80.8% and 71.7%, respectively. In multivariate Cox analysis, the longer interval was associated with an increased risk of mortality (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.01-2.02; p = 0.046) and recurrence (HR, 1.50; 95% CI, 1.12-1.99; p = 0.006). There was an interaction between the molecular subtype and the surgery interval for OS (pinteraction = 0.014) and RFS (pinteraction = 0.027). After PSM, no significant difference in OS (p = 0.180) and RFS (p = 0.069) was observed between the two groups. CONCLUSION: Among LABC patients with a poor response, those with a longer interval between NAC and surgery had worse OS and RFS. The results indicate that these patients should receive modified radical surgery timely, which may in turn improve their prognosis.

Impact of high-altitude hypoxia on Helicobacter pylori-induced gastritis pathological manifestations and inflammatory responses.

BACKGROUND: Chronic gastritis caused by Helicobacter pylori (Hp) infection is a common gastrointestinal disorder. Despite the high prevalence of Hp infection and chronic gastritis in the Tibetan Plateau, there is a lack of studies elucidating the influence of plateau hypoxia on Hp-induced gastritis. This study aimed to investigate the impact of high-altitude hypoxia on Hp-induced gastritis, particularly focusing on pathological manifestations and inflammatory responses. METHODS: This study was conducted from July 2023 to March 2024 at the Department of Gastroenterology, Affiliated Hospital of Qinghai University. Ninety patients diagnosed with chronic gastritis were enrolled in the study and divided into four groups based on their residential altitude and Hp infection status. Data on endoscopic and pathological characteristics were collected, along with serum oxidative stress and inflammatory markers. RESULTS: Patients with Hp gastritis exhibit distinctive features in the gastric mucosa, including diffuse erythema, enlarged folds, and white turbid mucus during endoscopy. Notably, individuals with Hp gastritis at high altitudes show a higher prevalence of diffuse erythema and enlarged folds. Pathological analysis reveals that these patients have elevated gastric mucosal inflammation scores and increased chronic and active inflammation. Furthermore, individuals with Hp gastritis at high altitudes demonstrate elevated levels of serum TNF-α, IL-1ß, IL-6, and MDA, as well as reduced serum SOD and GSH-Px activities. CONCLUSIONS: High-altitude hypoxia may exacerbate gastric mucosal damage by enhancing oxidative stress and inflammatory response induced by Hp infection.

Combining hybrid cell membrane modified magnetic nanoparticles and inverted microfluidic chip for in situ CTCs capture and inactivation.

Circulating tumor cells (CTCs) serve as crucial indicators for tumor occurrence, progression, and prognosis monitoring. However, achieving high sensitivity and high purity capture of CTCs remains challenging. Additionally, in situ capture and synchronous clearance hold promise as methods to impede tumor metastasis, but further exploration is needed. In this study, biomimetic cell membrane-coated magnetic nanoparticles (NPs) were designed to address the issue of nonspecific adsorption of capture probes by the immune system during blood circulation. Membranes from human breast cancer cells (tumor cell membranes, TMs) and leukocytes (white blood cell membranes, WMs) were extracted and fused to form a hybrid membrane (HM), which was further modified onto the surface of porous magnetic NPs loaded with indocyanine green (ICG). The incorporation of TM enhanced the material's target specificity, thus increasing capture efficiency, while WM coating reduced interference from homologous white blood cells (WBCs), further enhancing capture purity. Additionally, in conjunction with our novel inverted microfluidic chip, this work introduces the first use of polymer photonic crystals as the capture interface for CTCs. Besides providing an advantageous surface structure for CTC attachment, the 808 nm photonic bandgap effectively amplifies the 808 nm excitation light at the capture surface position. Therefore, upon capturing CTCs, the ICG molecules in the probes facilitate enhanced photothermal (PTT) and photodynamic (PDT) synergistic effects, directly inactivating the captured CTCs. This method achieves capture efficiency and purity exceeding 95% and permits in situ inactivation post-capture, providing an important approach for future research on impeding tumor metastasis in vivo.

Fasting-Mimicking Diet Facilitates Anti-tumor Therapeutic Effects by Nutrient-Sensitive Nanocomposites.

Cancer cells support their uncontrolled proliferation primarily by regulating energy metabolism. Inhibiting tumor growth by blocking the supply of nutrients is an effective treatment strategy. Fasting-mimicking diet (FMD), as a low-calorie, low-protein, low-sugar, high-fat diet, can effectively reduce the nutrient supply to tumor cells. However, the significant biological barrier presented by the tumor microenvironment imposes greater demands and challenges for drug design. This study constructs the multifunctional nanocomposite ZnFe2O4@TiO2@CHC@Orl-FA (ZTCOF), which has great potential to overcome the aforementioned drawbacks. ZnFe2O4@TiO2 could produce 1O2 with ultrasound, and stimulate the Fenton-like conversion of endogenous H2O2 to ·OH, achieving a combined therapeutic effect of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). Orl (Orlistat) and CHC (α-cyano-4-hydroxycinnamic acid) not only block tumor cell energy metabolism but also increase sensitivity to reactive oxygen species, enhancing the cytotoxic effect on tumor cells. Furthermore, combining the treatment strategies with FMD condition control can further inhibit cancer cell energy metabolism, achieving significant synergistic anti-tumor therapy. Both in vitro and in vivo experiments confirm that ZTCOF with SDT/CDT/starvation can achieve effective tumor suppression and destruction. This work provides theoretical and technical support for anti-tumor multimodal synergistic therapy.

Biofilm microenvironment-activated multimodal therapy nanoplatform for effective anti-bacterial treatment and wound healing.

Antimicrobial drug development faces challenges from bacterial resistance, biofilms, and excessive inflammation. Here, we design an intelligent nanoplatform utilizing mesoporous silica nanoparticles doped with copper ions for loading copper sulfide (DM/Cu2+-CuS). The mesoporous silica doped with tetrasulfide bonds responds to the biofilm microenvironment (BME), releasing Cu2+ions, CuS along with hydrogen sulfide (H2S) gas. The release of hydrogen sulfide within 72 h reached 793.5 µM, significantly higher than that observed with conventional small molecule donors. H2S induces macrophages polarization towards the M2 phenotype, reducing inflammation and synergistically accelerating endothelial cell proliferation and migration with Cu2+ions. In addition, H2S disrupts extracellular DNA within biofilms, synergistically photothermal enhanced peroxidase-like activity of CuS to effectively eradicate biofilms. Remarkably, DM-mediated consumption of endogenous glutathione enhances the anti-biofilm activity of H2S and improves oxygen species (ROS) destruction efficiency. The combination of photothermal therapy (PTT), chemodynamic therapy (CDT), and gas treatment achieves sterilization rates of 99.3 % and 99.6 % against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), respectively, in vitro under 808 nm laser irradiation. Additionally, in vivo experiments demonstrate a significant biosafety and antibacterial potential. In summary, the H2S donor developed in this study exhibits enhanced biocompatibility and controlled release properties. By integrating BME-responsive gas therapy with antibacterial ions, PTT and CDT, a synergistic multimodal strategy is proposed to offer new therapeutic approaches for wound healing. STATEMENT OF SIGNIFICANCE: The advanced DMOS/Cu2+-CuS (DMCC) multimodal therapeutic nanoplatform has been developed for the treatment of drug-resistant bacterial wound infections and has exhibited enhanced therapeutic efficacy through the synergistic effects of photothermal therapy, chemodynamic therapy, Cu2+ions, and H2S. The DMCC exhibited exceptional biocompatibility and could release CuS, Cu2+, and H2S in response to elevated concentrations of glutathione within the biofilm microenvironment. H2S effectively disrupted the biofilm structure. Meanwhile, peroxidase activity of CuS combined with GSH-mediated reduction of Cu2+ to Cu+ generated abundant hydroxyl radicals under acidic conditions, leading to efficient eradication of pathogenic bacteria. Furthermore, both H2S and Cu2+ could modulate M2 macrophages polarization and regulate immune microenvironment dynamics. These strategies collectively provided a novel approach for developing antibacterial nanomedical platforms.

Multi-mechanism antitumor/antibacterial effects of Cu-EGCG self-assembling nanocomposite in tumor nanotherapy and drug-resistant bacterial wound infections.

Chemotherapy and surgery stand as primary cancer treatments, yet the unique traits of the tumor microenvironment hinder their effectiveness. The natural compound epigallocatechin gallate (EGCG) possesses potent anti-tumor and antibacterial traits. However, the tumor's adaptability to chemotherapy due to its acidic pH and elevated glutathione (GSH) levels, coupled with the challenges posed by drug-resistant bacterial infections post-surgery, impede treatment outcomes. To address these challenges, researchers strive to explore innovative treatment strategies, such as multimodal combination therapy. This study successfully synthesized Cu-EGCG, a metal-polyphenol network, and detailly characterized it by using synchrotron radiation and high-resolution mass spectrometry (HRMS). Through chemodynamic therapy (CDT), photothermal therapy (PTT), and photodynamic therapy (PDT), Cu-EGCG showed robust antitumor and antibacterial effects. Cu+ in Cu-EGCG actively participates in a Fenton-like reaction, generating hydroxyl radicals (·OH) upon exposure to hydrogen peroxide (H2O2) and converting to Cu2+. This Cu2+ interacts with GSH, weakening the oxidative stress response of bacteria and tumor cells. Density functional theory (DFT) calculations verified Cu-EGCG's efficient GSH consumption during its reaction with GSH. Additionally, Cu-EGCG exhibited outstanding photothermal conversion when exposed to 808 nm near-infrared (NIR) radiation and produced singlet oxygen (1O2) upon laser irradiation. In both mouse tumor and wound models, Cu-EGCG showcased remarkable antitumor and antibacterial properties.

Effect of administration routes of oxytocin on hemoglobin in neonates with delayed umbilical cord clamping: a multi-centre randomized controlled clinical trial.

PURPOSE: To evaluate the effect of intravenous infusion versus intramyometrial injection of oxytocin on hemoglobin levels in neonates with delayed umbilical cord clamping during cesarean section. METHODS: The multi-centre randomized controlled trial was performed at three hospitals from February to June 2023. Women with term singleton gestations scheduled for cesarean delivery were allocated to receive an intravenous infusion of 10 units of oxytocin or a myometrial injection of 10 units of oxytocin during the surgery. The primary outcome was neonatal hemoglobin at 48 to 96 h after birth. Secondary outcomes were side-effects of oxytocin, postpartum haemorrhage, phototherapy for jaundice, feeding at 1 month, maternal and neonatal morbidity and re-admissions. RESULTS: A total of 360 women were randomized (180 women in each group). The mean neonatal hemoglobin did not show a significant difference between the intravenous infusion group (194.3 ± 21.7 g/L) and the intramyometrial groups (195.2 ± 24.3 g/L) (p = 0.715). Secondary neonatal outcomes, involving phototherapy for jaundice, feeding at 1 month and neonatal intensive care unit admission were similar between the two groups. The maternal outcomes did not differ significantly between the two groups, except for a 200 mL higher intraoperative infusion volume observed in the intravenous group compared to the intramyometrial group. CONCLUSION: Among women undergoing elective cesarean delivery of term singleton pregnancies, there was no significant difference in neonatal hemoglobin at 48 to 96 h after birth between infants with delayed cord clamping, whether the oxytocin was administrated by intravenous infusion or intramyometrial injection. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2300067953 (1 February 2023).

Transcatheter arterial perfusion chemotherapy combined with lipiodol chemoembolization for advanced colorectal cancer complicated by obstruction.

Background: Obstruction is a common complication of advanced colorectal cancer. This study was aimed at investigating the safety, efficacy, and feasibility of transcatheter arterial perfusion chemotherapy combined with lipiodol chemoembolization for treating advanced colorectal cancer complicated by obstruction. Patients and methods: This retrospective analysis was conducted using clinical data of patients with advanced colorectal cancer who received arterial infusion chemotherapy combined with lipiodol chemoembolization treatment at our center. Treatment efficacy was evaluated in terms of obstruction-free survival and overall survival, and treatment complications were monitored. Results: Fifty-four patients with colorectal cancer complicated by obstruction were included. All patients successfully underwent transcatheter arterial infusion combined with lipiodol chemoembolization treatment. The average lipiodol dose administered was 2.62 ± 1.45 ml (0.5-5.5 ml). No serious complications such as perforation or tumor dissemination occurred. The clinical success rate was 83.3% (45/54). One month after treatment, the objective response rate (ORR) and disease control rate (DCR) were 66.67% and 88.9%, respectively. The median obstruction-free survival was 5.0 months. No serious adverse events occurred. As of the last follow-up, 6 patients survived, 44 died, and 4 were lost to follow-up. Conclusion: Our findings revealed that transcatheter arterial infusion chemotherapy combined with lipiodol chemoembolization is safe and effective for treating advanced colorectal cancer complicated by obstruction. It may serve as a new treatment strategy for patients with advanced colorectal cancer complicated by obstruction.

"Three Musketeers" Enhances Photodynamic Effects by Reducing Tumor Reactive Oxygen Species Resistance.

Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) has been widely used in the treatment of a variety of tumors. Compared with other therapeutic methods, this treatment has the advantages of high efficiency, strong penetration, and controllable treatment range. PDT kills tumors by generating a large amount of reactive oxygen species (ROS), which causes oxidative stress in the tumor. However, this killing effect is significantly inhibited by the tumor's own resistance to ROS. This is because tumors can either deplete ROS by high concentration of glutathione (GSH) or stimulate autophagy to eliminate ROS-generated damage. Furthermore, the tumor can also consume ROS through the lactic acid metabolic pathway, ultimately hindering therapeutic progress. To address this conundrum, we developed a UCNP-based nanocomposite for enhanced PDT by reducing tumor ROS resistance. First, Ce6-doped SiO2 encapsulated UCNPs to ensure the efficient energy transfer between UCNPs and Ce6. Then, the biodegradable tetrasulfide bond-bridged mesoporous organosilicon (MON) was coated on the outer layer to load chloroquine (CQ) and α-cyano4-hydroxycinnamic acid (CHCA). Finally, hyaluronic acid was utilized to modify the nanomaterials to realize an active-targeting ability. The obtained final product was abbreviated as UCNPs@MON@CQ/CHCA@HA. Under 980 nm laser irradiation, upconverted red light from UCNPs excited Ce6 to produce a large amount of singlet oxygen (1O2), thus achieving efficient PDT. The loaded CQ and CHCA in MON achieved multichannel enhancement of PDT. Specifically, CQ blocked the autophagy process of tumor cells, and CHCA inhibited the uptake of lactic acid by tumor cells. In addition, the coated MON consumed a high level of intracellular GSH. In this way, these three functions complemented each other, just as the "three musketeers" punctured ROS resistance in tumors from multiple angles, and both in vitro and in vivo experiments had demonstrated the elevated PDT efficacy of nanomaterials.

Biodegradable pyroptosis inducer with multienzyme-mimic activity kicks up reactive oxygen species storm for sensitizing immunotherapy.

Triggering pyroptosis is a major new weathervane for activating tumor immune response. However, biodegradable pyroptosis inducers for the safe and efficient treatment of tumors are still scarce. Herein, a novel tumor microenvironment (TME)-responsive activation nanoneedle for pyroptosis induction, copper-tannic acid (CuTA), was synthesized and combined with the sonosensitizer Chlorin e6 (Ce6) to form a pyroptosis amplifier (CuTA-Ce6) for dual activation and amplification of pyroptosis by exogenous ultrasound (US) and TME. It was demonstrated that Ce6-triggered sonodynamic therapy (SDT) further enhanced the cellular pyroptosis caused by CuTA, activating the body to develop a powerful anti-tumor immune response. Concretely, CuTA nanoneedles with quadruple mimetic enzyme activity could be activated to an "active" state in the TME, destroying the antioxidant defense system of the tumor cells through self-destructive degradation, breaking the "immunosilent" TME, and thus realizing the pyroptosis-mediated immunotherapy with fewer systemic side effects. Considering the outstanding oxygen-producing capacity of CuTA and the distinctive advantages of US, the sonosensitizer Ce6 was attached to CuTA via an amide reaction, which further amplified the pyroptosis and sensitized pyroptosis-induced immunotherapy with the two-pronged strategy of CuTA enzyme-catalyzed cascade and US-driven SDT pathway to generate a "reactive oxygen species (ROS) storm". Conclusively, this work provided a representative paradigm for achieving safe, reliable and efficient pyroptosis, which was further enhanced by SDT for more robust immunotherapy.

Topological Electronic Transition Contributing to Improved Thermoelectric Performance in p-Type Mg3Sb2- xBix Solid Solutions.

Topological electronic transition is the very promising strategy for achieving high band degeneracy (NV) and for optimizing thermoelectric performance. Herein, this work verifies in p-type Mg3Sb2- xBix that topological electronic transition could be the key mechanism responsible for elevating the NV of valence band edge from 1 to 6, leading to much improved thermoelectric performance. Through comprehensive spectroscopy characterizations and theoretical calculations of electronic structures, the topological electronic transition from trivial semiconductor is unambiguously demonstrated to topological semimetal of Mg3Sb2- xBix with increasing the Bi content, due to the strong spin-orbit coupling of Bi and the band inversion. The distinct evolution of Fermi surface configuration and the multivalley valence band edge with NV of 6 are discovered in the Bi-rich compositions, while a peculiar two-step band inversion is revealed for the first time in the end compound Mg3Bi2. As a result, the optimal p-type Mg3Sb0.5Bi1.5 simultaneously obtains a positive bandgap and high NV of 6, and thus acquires the largest thermoelectric power factor of 3.54 and 6.93 µW cm-1 K-2 at 300 and 575 K, respectively, outperforming the values in other compositions. This work provides important guidance on improving thermoelectric performance of p-type Mg3Sb2- xBix utilizing the topological electronic transition.

Ultra-small Janus nanoparticle-induced activation of ferroptosis for synergistic tumor immunotherapy.

Ferroptosis induced by lipid peroxide (LPO) accumulation is an effective cell death pathway for cancer therapy. However, how to effectively induce ferroptosis at tumor sites and improve its therapeutic effectiveness remains challenging. Here, MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex with tumor-specific targeting and TME response is constructed to overcome immunosuppressive tumor microenvironment (TME) to potentiate the curative effect of ferroptosis by coupling the immune checkpoint indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, and hyaluronic acid (HA) to novel ultra-small MnFe2O4@NaGdF4 (MG) nanoparticles with a Janus structure. Firstly, tumor site-precise delivery of MG and NLG919 is achieved with HA targeting. Secondly, MG acts as a magnetic resonance imaging contrast agent, which not only has a good photothermal effect to realize tumor photothermal therapy, but also depletes glutathione and catalyzes the production of reactive oxygen species from endogenous H2O2, which effectively promotes the accumulation of LPO and inhibits the expression of glutathione peroxidase 4, achieving enhanced ferroptosis. Thirdly, NLG919 inhibits the differentiation of Tregs by blocking the tryptophan/kynurenine immune escape pathway, thereby reversing immunosuppressive TME together with the Mn2+-activated cGAS-STING pathway. This work contributes new perspectives for the development of novel ultra-small Janus nanoparticles to reshape immunosuppressive TME and ferroptosis activation. STATEMENT OF SIGNIFICANCE: The Janus structured MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex was synthesized, which can realize the precise delivery of T1/T2 contrast agents MnFe2O4@NaGdF4 (MG) and NLG919 at the tumor site under the ultra-small Janus structural characteristics and targeted molecule HA. The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention.

Chemical Synthesis of Fucosylated Chondroitin Sulfate Tetrasaccharide with Fucosyl Branch at the 6-OH of GalNAc Residue.

Fucosylated chondroitin sulfate is a unique glycosaminoglycan isolated from sea cucumbers, with excellent anticoagulant activity. The fucosyl branch in FCS is generally located at the 3-OH of D-glucuronic acid but, recently, a novel structure with α-L-fucose linked to the 6-OH of N-acetyl-galactosamine has been found. Here, using functionalized monosaccharide building blocks, we prepared novel FCS tetrasaccharides with fucosyl branches both at the 6-OH of GalNAc and 3-OH of GlcA. In the synthesis, the protective group strategy of selective O-sulfation, as well as stereoselective glycosylation, was established, which enabled the efficient synthesis of the specific tetrasaccharide compounds. This research enriches knowledge on the structural types of FCS oligosaccharides and facilitates the exploration of the structure-activity relationship in the future.