A manganese-doped layered double hydroxide loaded with lactate oxidase and DNA repair inhibitors for synergistically enhanced tumor immunotherapy.

Tumor immunotherapy has gained more and more attention in tumor treatment. However, the accumulation of lactic acid in tumor tissue inhibits the response of immune cells to form an immunosuppressive microenvironment (ISME). To reverse the ISME, an acid-responsive nanoplatform (termed as MLLN@HA) is reported for synergistically enhanced tumor immunotherapy. MLLN@HA is constructed by the co-loading of lactate oxidase (LOX) and DNA repair inhibitor (NU7441) in a manganese-doped layered double hydroxide (Mn-LDH), and then modified with hyaluronic acid (HA) for tumor-targeted delivery. After endocytosis by tumor cells, MLLN@HA decomposes and releases LOX, NU7441 and Mn2+ ions in the acidic tumor microenvironment. The released LOX catalyzes the conversion of lactic acid into hydrogen peroxide (H2O2), which not only alleviates the ISME, but also provides reactants for the Mn2+-mediated Fenton-like reaction to enhance chemodynamic therapy (CDT). Released NU7441 prevents CDT-induced DNA damage from being repaired, thereby increasing double-stranded DNA (dsDNA) fragments within tumor cells. Importantly, the released Mn2+ ions enhance the sensitivity of cyclic GMP-AMP synthase (cGAS) to dsDNA fragments, and activate the stimulator of interferon genes (STING) to induce an anti-tumor immune response. Such an orchestrated immune-boosting strategy ultimately achieves effective tumor growth inhibition and prevents tumor lung metastasis. STATEMENT OF SIGNIFICANCE: To improve the efficacy of tumor immunotherapy, an innovative acid-responsive MLLN@HA nanoplatform was developed for synergistically enhanced tumor immunotherapy. The MLLN@HA actively targets to tumor cells through the interaction of HA with CD44, and then degrades to release LOX, NU7441 and Mn2+ ions in the acidic tumor microenvironment. The released LOX generates H2O2 for the Mn2+-mediated Fenton reaction and reverses the ISME by consuming lactate. NU7441 prevents DNA damage repair, leading to an increased concentration of free DNA fragments, while Mn2+ ions activate the cGAS-STING pathway, enhancing the systemic anti-tumor immune response. The orchestrated immune-boosting nanoplatform effectively inhibits tumor growth and lung metastasis, presenting a promising strategy for cancer treatment.

Allomelanin-based biomimetic nanotherapeutics for orthotopic glioblastoma targeted photothermal immunotherapy.

Immune checkpoint blockade (ICB) therapy has shown great potential in the treatment of malignant tumors, but its therapeutic effect on glioblastoma (GBM) is unsatisfactory because of the low immunogenicity and T cell infiltration, as well as the presence of blood-brain barrier (BBB) that blocks most of ICB agents to the GBM tissues. Herein, we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted photothermal therapy (PTT) and ICB synergistic therapy by loading immune checkpoint inhibitor CLP002 into the allomelanin nanoparticles (AMNPs) and followed by coating cancer cell membranes (CCM). The resulting AMNP@CLP@CCM can successfully cross the BBB and deliver CLP002 to GBM tissues due to the homing effect of CCM. As a natural photothermal conversion agent, AMNPs are used for tumor PTT. The increased local temperature by PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells. Importantly, PTT can effectively stimulate immunogenic cell death to induce tumor-associated antigen exposure and promote T lymphocyte infiltration, which can further amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Therefore, AMNP@CLP@CCM has great potential for the treatment of orthotopic GBM by PTT and ICB synergistic therapy. STATEMENT OF SIGNIFICANCE: The effect of ICB therapy on GBM is limited by the low immunogenicity and insufficient T-cell infiltration. Here we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted PTT and ICB synergistic therapy. In this nanoplatform, AMNPs are used as both photothermal conversion agents for PTT and nanocarriers for CLP002 delivery. PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells by increasing local temperature. Additionally, PTT also induces tumor-associated antigen exposure and promotes T lymphocyte infiltration to amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Thus, this nanoplatform holds great potential for orthotopic GBM treatment.

Investigation of Microstructure and Wear Properties of Precipitates-Strengthened Cu-Ni-Si-Fe Alloy.

Based on multi-component alloys using precipitation hardening, a Cu-Ni-Si-Fe copper alloy was prepared and studied for hardness, electrical conductivity, and wear resistance. Copper Nickel Silicon (Cu-Ni-Si) intermetallic compounds were observed as precipitates, leading to an increase in mechanical and physical properties. Further, the addition of Fe was discussed in intermetallic compound formation. Moreover, microstructures, age hardening, and dry sliding wear resistances of the present alloy were analyzed and compared with C17200 beryllium copper. The results showed that the present alloy performed extraordinarily, with 314 HV in hardness and 22.2 %IACS in conductivity, which is almost similar to C17200 alloy. Furthermore, the dry sliding wear resistance of the present alloy was 2199.3 (m/MPa·mm3) at an ambient temperature, leading to an improvement of 208% compared with the C17200 alloy.

Multifunctional nanoreactors with nutrient consumption and ROS generation capabilities for antibacterial and skin repair.

Bacterial wound infection has brought a serious threat to human health and caused huge economic losses. Attempts to develop biomaterials with excellent antibacterial effects are meaningful to promote wound healing. Herein, we report a multifunctional nanoreactor with nutrient consumption and reactive oxygen species (ROS) generation capabilities for antibacterial and skin wound repair. The nanoreactor was constructed by the encapsulation of glucose oxidase (GOx) into a Cu2+-doped zeolite-based imidazole framework (ZIF-8) through a one-pot synthesis method. The nanoreactor not only consumes the nutrients of bacteria by the GOx-driven oxidation reaction, but also generates highly toxic hydroxyl radicals (˙OH) to kill bacteria via a Cu+-mediated Fenton-like reaction. Moreover, Zn2+ released from the nanoreactor is also capable of exhibiting synergistic antibacterial activity. In addition to mediating Fenton-like reactions, Cu2+ promotes angiogenesis to accelerate wound healing. Thus, the multifunctional nanoreactor has the ability to cut off the nutrient supply and starve the bacteria, produce ROS to kill bacteria, and promote angiogenesis to accelerate wound healing, enabling it to be promising for the treatment of wound infection.

Deformation-activated recrystallization twin: New twinning path in pure aluminum enabled by cryogenic and rapid compression.

Bulk aluminum rarely forms deformation or annealing twins owing to its high stacking fault energy. We report a novel twinning mechanism mediated by dynamic recrystallization in 6N pure aluminum under high strain rate (∼1.3 × 104 s-1) impact at a cryogenic temperature (77 K). Discontinuous dynamic recrystallization occurs during rapid severe plastic deformation and generates inhomogeneous microstructures exhibiting low-angle and high-angle grain boundaries. Unexpectedly, Σ3 twin boundaries were able to develop during dynamic recrystallization. Although these recrystallization twins have similar morphology as that of annealing twins, their formation relies on deformation activation instead of thermal activation, which was suppressed by the cryogenic experiment. Besides, strong orientation dependence was observed for formation of these novel twins. Beyond annealing and deformation twin, deformation-activated recrystallization twin is a new path for pure aluminum twinning.