Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia.

Cuproptosis, a copper-dependent cell death process, has been confirmed to further activate the immune response and mediate the immune resistance. However, hypoxic tumor microenvironment hampers cuproptosis sensitivity and suppresses the body's antitumor immune response. Herein, we have successfully immobilized and functionalized catalase (CAT) with long single-stranded DNA containing polyvalent CpG sequences through rolling circle amplification (RCA) techniques, obtaining an enzyme-cored spherical nucleic acid nanoplatform (CAT-ecSNA-Cu) to deliver copper ions for cuproptosis. The presence of long-stranded DNA-protected CAT enhances mitochondrial respiration by catalyzing the conversion of H2O2 to O2, thereby sensitizing cuproptosis. Meanwhile, increased tumor oxygenation suppresses the expression of the hypoxia-inducible factor-1 (HIF-1) protein, resulting in the alleviation of the immunosuppressive tumor microenvironment. Of note, cuproptosis induces immunogenic cell death (ICD), which facilitates dendritic cell (DC) maturation and enhances antigen presentation through polyCpG-supported Toll-like receptor 9 (TLR9) activation. Furthermore, cuproptosis-induced PD-L1 upregulation in tumor cells complements checkpoint blockers (αPD-L1), enhancing antitumor immunity. The strategy of enhancing cuproptosis-mediated antitumor immune responses by alleviating hypoxia effectively promotes the activation and proliferation of effector T cells, ultimately leading to long-term immunity against cancer.

Polyvalent Aptamer Nanodrug Conjugates Enable Efficient Tumor Cuproptosis Therapy Through Copper Overload and Glutathione Depletion.

Cuproptosis, a recently identified form of copper-dependent cell death, shows promising tumor suppressive effects with minimal drug resistance. However, its therapeutic efficacy is hampered by its dependence on copper ions and the glutathione (GSH)-rich microenvironment in tumors. Here, we have developed polyvalent aptamer nanodrug conjugates (termed CuPEs@PApt) with a nucleosome-like structure to improve tumor cuproptosis therapy by exploiting mitochondrial copper overload and GSH depletion. Polyvalent aptamer (PApt), comprising polyvalent epithelial cell adhesion molecule aptamers for tumor targeting and repetitive PolyT sequences for copper chelation, facilitates efficient loading and targeted delivery of copper peroxide-Elesclomol nanodots (CuPEs). Upon internalization by tumor cells, Elesclomol released from CuPEs@PApt accumulates copper ions in mitochondria to initiate cuproptosis, while lysosomal degradation of CuP nanodots generates exogenous Cu2+ and H2O2, triggering a Fenton-like reaction for GSH depletion to enhance cuproptosis. In vitro and in vivo experiments confirm the efficacy of this strategy in inducing tumor cell cuproptosis and immunogenic cell death, the latter contributing to the activation of the antitumor immune response for synergistic tumor growth inhibition.

A Cardiac-Targeted Nanozyme Interrupts the Inflammation-Free Radical Cycle in Myocardial Infarction.

Severe systemic inflammation following myocardial infarction (MI) is a major cause of patient mortality. MI-induced inflammation can trigger the production of free radicals, which in turn ultimately leads to increased inflammation in cardiac lesions (i.e., inflammation-free radicals cycle), resulting in heart failure and patient death. However, currently available anti-inflammatory drugs have limited efficacy due to their weak anti-inflammatory effect and poor accumulation at the cardiac site. Herein, a novel Fe-Cur@TA nanozyme is developed for targeted therapy of MI, which is generated by coordinating Fe3+ and anti-inflammatory drug curcumin (Cur) with further modification of tannic acid (TA). Such Fe-Cur@TA nanozyme exhibits excellent free radicals scavenging and anti-inflammatory properties by reducing immune cell infiltration, promoting macrophage polarization toward the M2-like phenotype, suppressing inflammatory cytokine secretion, and blocking the inflammatory free radicals cycle. Furthermore, due to the high affinity of TA for cardiac tissue, Fe-Cur@TA shows an almost tenfold greater in cardiac retention and uptake than Fe-Cur. In mouse and preclinical beagle dog MI models, Fe-Cur@TA nanozyme preserves cardiac function and reduces scar size, suggesting promising potential for clinical translation in cardiovascular disease.

A Single-Atom Manganese Nanozyme Mn-N/C Promotes Anti-Tumor Immune Response via Eliciting Type I Interferon Signaling.

Tumor microenvironment (TME)-induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single-atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here, a single-atom manganese (Mn)-N/C nanozyme is constructed. Mn-N/C catalyzes the conversion of cellular H2O2 to ∙OH through a Fenton-like reaction and enables the sufficient generation of reactive oxygen species (ROS), which induces immunogenic cell death (ICD) of tumor cells and significantly promotes CD8+T anti-tumor immunity. Moreover, RNA sequencing analysis reveals that Mn-N/C treatment activates type I interferon (IFN) signaling, which is critical for Mn-N/C-mediated anti-tumor immune response. Mechanistically, the release of cytosolic DNA and Mn2+ triggered by Mn-N/C collectively activates the cGAS-STING pathway, subsequently stimulating type I IFN induction. A highly efficient single-atom nanozyme, Mn-N/C, which enhances anti-tumor immune response and exhibits synergistic therapeutic effects when combined with the anti-PD-L1 blockade, is proposed.

Influences of offshore background wind on the formation of sea-land breeze and the characteristics of pollutant diffusion.

The formation of sea-land breeze (SLB) is primarily affected by background wind and temperature difference between the sea and nearby land. Because the intensity of sea breeze is significantly stronger than that of land breeze, land breeze may result in more accumulated pollutants under the condition of offshore background wind (OBW) than under the condition of no OBW in coastal areas. The formation process of sea-land breeze and the dispersion trajectory and accumulation effect of pollutants are studied under different velocities of OBW with the same sea-land temperature difference by employing computational fluid dynamics (CFD). The results reveal that the depth and the duration of sea breeze decrease with the increase of the velocity of OBW. The most unfavorable velocity of OBW (0.2 m s-1) exists when the concentration affected by OBW is higher than that by no OBW in coastal areas. The pollutants close to the ground will be blown to the inland by sea breeze when the velocity of OBW is less than 1.0 m s-1. When the velocity of OBW is larger than 2.0 m s-1, the pollutants will not occur on the inland due to the influence of OBW.

[Indoor Formaldehyde and Benzene Series in Shanghai Residences and Their Associations with Building Characteristics and Lifestyle Behaviors].

From March 2013 to December 2014, we on-site inspected indoor concentrations of formaldehyde and a benzene series in 454 children's bedrooms that were decorated earlier than one year before our inspection. Large differences existed in the formaldehyde and benzene-series concentrations among individual bedrooms. Bedrooms that were inspected in winter had significantly higher concentration of formaldehyde than bedrooms that were inspected in other seasons (P<0.001), but the benzene-series concentration had no significant seasonal difference. Among bedrooms that were inspected in spring, those using different materials as wall coverings had significant differences in concentrations of the benzene series. Among bedrooms that were inspected in summer, those using different materials as floor coverings had significant differences in concentrations of the benzene series (P<0.01). Among bedrooms that were inspected in autumn, those with>5 household bonsais had significantly higher concentrations of formaldehyde than other bedrooms did. Among bedrooms that were inspected in winter, those with frequent use of air humidifiers and those in which pets were kept had significantly higher concentrations of the benzene series than other bedrooms did (P<0.05). These results indicate that, after a long time since decoration, the types of household wall and floor covering materials still have certain relationships with indoor benzene-series levels and, compared to decoration materials, household ventilation perhaps has greater effect on indoor formaldehyde levels. The indoor benzene-series level perhaps has associations with indoor humidity level and the keeping of pets in households. Household bonsaies may have limited effect on indoor formaldehyde and benzene-series levels in residences that were decorated a long time ago.