Copper Deposition in Polydopamine Nanostructure to Promote Cuproptosis by Catalytically Inhibiting Copper Exporters of Tumor Cells for Cancer Immunotherapy.

Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.

Acidic and hypoxic tumor microenvironment regulation by CaO2-loaded polydopamine nanoparticles.

Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO2)-loaded nanostructure that can play a role of "one stone kill two birds", i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO2 loaded nanostructure. Specifically, CaO2-loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO2@mPDA-SH) can gradually accumulate in a tumor site. CaO2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO2@mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.

Arginine-Nanoenzyme with Timely Angiogenesis for Promoting Diabetic Wound Healing.

The successful treatment of diabetic wounds requires strategies that promote anti-inflammation, angiogenesis, and re-epithelialization of the wound. Excessive oxidative stress in diabetic ulcers (DUs) inhibits cell proliferation and hinders timely vascular formation and macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2, resulting in a persistent inflammatory environment and a nonhealing wound. We designed arginine-nanoenzyme (FTA) with mimic-catalase and arginine-loading. 2,3,4-trihydroxy benzaldehyde and arginine (Arg) were connected by a Schiff base bond, and the nanoassembly of Arg to FTA was driven by the coordination force between a ferric ion and polyphenol and noncovalent bond force such as a hydrogen bond. FTA could remove excess reactive oxygen species at the wound site in situ and convert it to oxygen to improve hypoxia. Meanwhile, Arg was released and catalytically metabolized by NO synthase in M1 to promote vascular repair in the early phase. In the late phase, the metabolite of Arg catalyzed by arginase in M2 was mainly ornithine, which played a vital role in promoting tissue repair, which implemented angiogenesis timely and prevented hypertrophic scars. Mechanistically, FTA activated the cAMP signaling pathway combined with reducing inflammation and ameliorating angiogenesis, which resulted in excellent therapeutic effects on a DU mice model.

Nanotechnology-enabled M2 macrophage polarization and ferroptosis inhibition for targeted inflammatory bowel disease treatment.

Transforming macrophages into the anti-inflammatory M2 phenotype could markedly strengthen inflammatory bowel disease (IBD) treatment, which is considered as a promising strategy. However, the high ferroptosis sensitivity of M2 macrophages, which decreases their activity, is a major stumbling block to this strategy. Therefore, promoting M2 polarization while simultaneously inhibiting ferroptosis to tackle this challenge is indispensable. Herein, a calcium­carbonate (CaCO3) mineralized liposome encapsulating a ferroptosis inhibitor (Fer-1) was developed (CaCO3@Lipo@Fer-1, CLF). The CaCO3 mineralized coating shields the liposomes to prevent the release of Fer-1 in circulation, while releasing Ca2+ in the acidic-inflammatory environment. This released Ca2+ promotes M2 polarization through the CaSR/AKT/ß-catenin pathway. The subsequently released Fer-1 effectively upregulates GSH and GPX4, scavenges reactive oxygen species, and inhibits ferroptosis in M2 macrophages. In vivo, CLF improved the targeting efficiency of IBD lesions (about 4.17-fold) through the epithelial enhanced permeability and retention (eEPR) effect and enhanced IBD therapy by increasing the M2/M1 macrophage ratio and inhibiting ferroptosis. We demonstrate that the synergistic regulation of macrophage polarization and ferroptosis sensitivity by this mineralized nanoinhibitor is a viable strategy for IBD therapy.

Arginine-assembly as NO nano-donor prevents the negative feedback of macrophage repolarization by mitochondrial dysfunction for cancer immunotherapy.

Repolarizing the tumor-associated macrophages (TAMs) towards the antitumoral M1-like phenotype has been a promising approach for cancer immunotherapy. However, the anti-cancer immune response is severely limited mainly by the repolarized M1-like macrophages belatedly returning to the M2-like phenotype (i.e., negative feedback). Inspired by nitric oxide (NO) effectively preventing repolarization of inflammatory macrophages in inflammatory diseases, herein, we develop an arginine assembly, as NO nano-donor for NO generation to prevent the negative feedback of the macrophage repolarization. The strategy is to first apply reversible tagging of hydrophobic terephthalaldehyde to create an arginine nano-assembly, and then load a toll-like receptor 7/8 agonist resiquimod (R848) (R848@Arg). Through this strategy, a high loading efficiency of 40 % for the arginine and repolarization characteristics for TAMs can be achieved. Upon the macrophage repolarization by R848, NO can be intracellularly generated from the released arginine by the upregulated inducible nitric oxide synthase. Mechanistically, NO effectively prevented the negative feedback of the repolarized macrophage by mitochondrial dysfunction via blocking oxidative phosphorylation. Notably, R848@Arg significantly increased the tumor inhibition ratio by 3.13-fold as compared to the free R848 by maintaining the M1-like phenotype infiltrating into tumor. The Arg-assembly as NO nano-donor provides a promising method for effective repolarization of macrophages.

Nanomedicine-mediated ferroptosis targeting strategies for synergistic cancer therapy.

Apoptosis-based treatment plays an important role in regulating the death of tumor cells (e.g., chemotherapy, radiotherapy, and immunotherapy). Nevertheless, cancer cells can escape surveillance from apoptosis-associated signaling by bypassing other biological pathways and thus result in considerable resistance to therapies. Significantly, ferroptosis, a newly identified type of regulated cell death that is characterized by iron-dependent and lipid peroxidation accumulation, has aroused great research interest in cancer therapy. Increasing approaches have been developed to induce ferroptosis of tumor cells, including using clinically approved drugs, experimentally used compounds, and nanomedicine formulations. More importantly, the emerging nanomedicine-based strategy has made great advances in tumor treatment because of the promising targeting efficacy and enhanced therapeutic effects. In this review, we mainly overview state-of-the-art research on nanomedicine-mediated ferroptosis targeting strategies for synergistic cancer therapies, such as immunotherapy, chemotherapy, radiotherapy, and photothermal therapy. The potential targeting mechanism of nanomedicine for ferroptosis induction was also included. Finally, the future development of nanomedicine in the field of ferroptosis-based cell death in tumor treatment will be envisioned, aiming to provide new insight for tumor treatment in the clinic.

NOX2 Enzyme Mimicking Nano-Networks Regulate Tumor-Associated Macrophages to Initiate Both Innate and Adaptive Immune Effects.

Macrophages, capable of both direct killing and antigen presentation, are crucial for the interplay between innate and adaptive immunity. However, strategies mainly focus on polarizing tumor-associated macrophages (TAMs) to M1 phenotype, while overlooking the inefficient antigen cross-presentation due to hyperactive hydrolytic protease within lysosomes which leads to antigen degradation. In light of the significant influence of reactive oxygen species (ROS) on TAMs' polarization and the inhibition of phagosomal proteolysis, a novel nanosystem termed OVA-Fe-GA (OFG) is engineered, drawing inspiration from the NOX2 enzyme's role. OFG integrates ovalbumin (OVA) and a network composed of Fe-gallic acid (GA), emulating the NOX2 enzyme's sequential ROS generation process ("O2 to O2 •- to H2 O2 /•OH"). Furthermore, it elucidates a biological mechanism that augments antigen cross-presentation by suppressing the expression of cysteine proteases. OFG restores the innate anti-tumor functionality of TAMs and significantly amplifies their antigen cross-presentation (4.5-fold compared to the PBS control group) in B16-OVA tumor-bearing mice. Notably, the infiltration and activity of intratumoral CD8+ T cells are enhanced, indicating an adaptive immune response. Moreover, OFG exhibits excellent photothermal properties, thereby fostering a system antitumor immune response. This study provides a promising strategy for initiating both innate and adaptive immunity via TAMs activation. This article is protected by copyright. All rights reserved.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) and Spike (S) Proteins Antagonize Host Type I Interferon Response.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and has infected more than 250 million people. A typical feature of COVID-19 is the lack of type I interferon (IFN-I)-mediated antiviral immunity in patients. However, the detailed molecular mechanisms by which SARS-CoV-2 evades the IFN-I-mediated antiviral response remain elusive. Here, we performed a comprehensive screening and identified a set of SARS-CoV-2 proteins that antagonize the IFN-I response. Subsequently, we characterized the mechanisms of two viral proteins antagonize IFN-I production and downstream signaling. SARS-CoV-2 membrane protein binds to importin karyopherin subunit alpha-6 (KPNA6) to inhibit interferon regulatory factor 3(IRF3) nuclear translocation. Further, the spike protein interacts with signal transducer and activator of transcription 1 (STAT1) to block its association with Janus kinase 1 (JAK1). This study increases our understanding of SARS-CoV-2 pathogenesis and suggests novel therapeutic targets for the treatment of COVID-19.