Search

Ion interference including copper (Cu+)/calcium (Ca2+) overload activate cell‐specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti‐tumor therapy. However, the complex metabolic environment and the powerful self‐protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS‐α‐CHCA&penthiopyrad@CaCO3‐RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu+/Ca2+ dual‐overload anti‐tumor therapy assisted by metabolic‐symbiosis‐destruction strategy, realizing the collapse of tumor self‐protection. Specifically, precise CuS and CaCO3 delivery triggered irreversible Cu+/Ca2+ dual‐overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α‐CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton‐like reaction of Cu+, enhancing the sensitivity of tumor cells to copper death and Ca2+ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross‐presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti‐tumor dual‐ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors. [ABSTRACT FROM AUTHOR]

Immune activation has been widely recognized to promote anti‐tumor effects in vivo. However, in previous anti‐tumor studies of combined photo/immunotherapy, the tumor apoptosis pathway is widely regarded as an independent process, which led to an incomplete understanding of the anti‐tumor mechanisms of the immune system during phototherapy. Herein, the decisive role of immune activation for the anti‐tumor effect of phototherapy and its specific mechanism, are investigated by preparing a melanin@chlorin e6@hyaluronic acid and oxidized Bletilla striata polysaccharide@NO‐donor (MCH‐OBN) nanoplatform, which integrated significant immune activation by phototherapy. The comparison of anti‐tumor effects between wild‐type mice and immunodeficient mice showed that effective phototherapy provided by the MCH‐OBN can not independently kill tumor cells in vivo, as it significantly depends on the immune activation. Furthermore, the activated immune system is demonstrated to destroy the tumor cell "barrier protection" by inhibiting the growth of cancer‐associated fibroblasts (CAFs), thereby ensuring the damage of heat, reactive oxygen species (ROS), and other components of phototherapy to the tumor. Thus, this work reveals for the first time the biological consequences of immune activation that determine the anti‐tumor effect of phototherapy by regulating CAF proliferation, which is of great significance for optimizing anti‐tumor clinical treatments through phototherapy. [ABSTRACT FROM AUTHOR]

Due to the persistent presence of Enterococcus faecalis biofilms in apical root canals, persistent endodontic infections (PEIs) have always been an intractable disease to solve. The conventional root canal disinfectants (e.g., calcium hydroxide, chlorhexidine) are arduous to scavenge the stubborn infection. With the progress of nanomedicine in the biomedical field, antimicrobial photodynamic therapy (aPDT) is emerging as a prospective anti-infective therapy for PEIs. Herein, quaternized chitosan (QCh) modified upconversion nanoparticles (UCNP)@SiO2/methylene blue (MB) are developed with enhanced antibacterial/biofilm performance for aPDT in PEIs. QCh is coated on the UCNP@SiO2/MB by testing the changes in diameter, chemical functional group, and charge. Interestingly, QCh also increases the conversion efficiency of UCNP to generate more reactive oxygen species (ROS). Furthermore, the prepared UCNP@SiO2/MB@QCh exhibits highly effective antibacterial activity against free E. faecalis and related biofilm in vitro and extracted teeth. Importantly, the additional QCh with positive charges enhance UCNP@SiO2/MB@QCh contact with E. faecalis (negative charges) through electrostatic interaction. Then, UCNP@SiO2/MB@QCh could stick close to the E. faecalis and generate ROS under the irradiation by a 980 nm laser. The in vitro cellular test shows that UCNP@SiO2/MB@QCh has acceptable cytocompatibility. Thus, UCNP@SiO2/MB@QCh could offer a novel strategy for the potential aPDT clinical applications in the treatment of PEIs. Schematic diagram of the preparation of UCNP@SiO2/MB@QCh and the following antibacterial effect. [ABSTRACT FROM AUTHOR]

Severe resistance of doxorubicin (DOX) caused by drug efflux and immunosuppression has led to a high treatment failure risk of breast cancer (BC). Compared with the single atom nanozymes, the bi‐single‐atomic nanozymes obtained through sequential single‐atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi‐single‐atom nanozymes (Zn/Cu‐BSAN‐DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H2O2 self‐supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn/Cu‐BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as “hexagonal” anti‐tumor warrior, Zn/Cu‐BSAN‐DOX NPs show great potential for multimodal DOX‐resistant BC therapy, which further expands the new preparation strategy and the clinical anti‐tumor application paradigm of single‐atom nanozymes. [ABSTRACT FROM AUTHOR]

Pathological scars (PS) are involved in the excessive response of inflammation and overactivation of myofibroblasts. Herein, a novel microneedle (MN) patch based on the adipose‐derived stem cell concentrated conditioned medium (ADSCC‐CM) cross‐linked keratin hydrogel is developed to load triamcinolone acetonide (TA), thereby achieving the dual‐drug delivery of ADSCC‐CM and TA to simultaneously reduce the inflammation and guide myofibroblast behaviors. Results not only confirm the ability of ADSCC‐CM to drive the formation of keratin‐based hydrogel, but also verify the dual‐drug release capacities of the hydrogel‐developed MNs (TA@AC‐MN). Using human hyperplastic scar fibroblast (HSF), the combination of ADSCC‐CM and TA demonstrates a pronounced synergistic effect in mitigating the detrimental effects of the inflammatory microenvironment on HSFs, including suppressing the production of reactive oxygen species and attenuating the expression of inflammatory factors. Compared with the clinically used TA, TA@AC‐MN promotes scar biomimetic repair (i.e., optimizing the proportion of collagen and increasing the tissue tensile strength). This study demonstrates that TA@AC‐MN has the capacity to provide a self‐managing and minimally invasive therapeutic strategy for PS. [ABSTRACT FROM AUTHOR]

Aims: Vulnerable plaque disruption in advanced atherosclerosis leads to acute thrombus and subsequent myocardial infarction and severely threatens human health. Necroptosis of macrophage involved in the necrotic core is one key factor for plaque vulnerability. Dihydrotanshinone I (DHT) is a natural diterpenoid isolated from Danshen demonstrating effective anti-inflammatory property. It is accepted that inflammation plays a crucial role in the process of atherogenesis. However, whether DHT prevents atherosclerosis is poorly understood. Here, we investigated the effect of DHT on vulnerable plaque in an apolipoprotein E-deficient (ApoE−/−) mice model of atherosclerosis and the underlying protective mechanisms. Results: In the in vitro experiment, first LPS/ZVAD (LPS, lipopolysaccharide; ZVAD, ZVAD-FMK, a cell-permeable pan-caspase inhibitor) stimulated necroptosis of macrophage in a receptor-interacting protein 3 (RIP3)-dependent pathway, which was regulated by Toll-like receptor 4 (TLR4) dimerization. Further study illustrated that activated RIP3 evoked endoplasmic reticulum stress as well as reactive oxygen species generation. Both DHT and RIP3 silence reversed the above phenomena. In the in vivo experiment, aorta and serum samples were collected to determine features of plaque stability, including plaque size, necrotic core area, as well as collagen content in fibrous cap and the expression of related protein molecules. Both DHT and RIP3 inhibitor GSK872 significantly enhanced plaque stability in ApoE−/− mice by reducing oxidative stress, shrinking necrotic core area, increasing collagen content, and decreasing RIP3 expression. Innovation and Conclusion: Our study showed that DHT may stabilize vulnerable plaque by suppressing RIP3-mediated necroptosis of macrophage, which indicates its potential application as a lead compound for cardiovascular treatments, especially for advanced atherosclerosis. Antioxid. Redox Signal. 34, 351–363. [ABSTRACT FROM AUTHOR]