Photothermal nanocomposite reactivate "immune-hot" for triple-negative breast cancer treatment via glutamine metabolism reprograming.

Herein, a photothermal nanocomposite PAI@CB839 nanoparticles (NPs) was constructed to perform a heat-immune therapy for triple-negative breast cancer (TNBC). Firstly, a photothermal agent animated IR780 was modified on a mPEG-NH2 using 4,4'-dicarboxylazobenzene as a linker. The synthesized PAI exhibited superior photothermal efficiency of the IR780 even after assembling in water. As a functional carrier, PAI was used to load and deliver the glutaminase inhibitor CB839 to tumor tissue. In the hypoxic environment of tumor cells, the azo bond would break, triggering the release of cargo. Upon irradiation, the outstanding photothermal properties of IR780 resulted in tumor cell damage. This process could promote immunogenic cell death and program tumor to "immune-hot" condition. Concurrently, CB839 strengthened the antitumor immune response by remodulating the immunosuppressive TME through disturbing Glu abnormal metabolism, which further inhibited TNBC growth and metastasis. In conclusion, PAI@CB839 NPs exhibited great antitumor efficiency, which pave a new way for TNBC therapeutic regimen development.

Recent Biomedical Applications of Functional Materials Based on Polyhedral Oligomeric Silsesquioxane (POSS).

Polyhedral oligomeric silsesquioxane (POSS) is a 3D, cage-like nanoparticle with an inorganic Si-O-Si core and eight tunable corner functional groups. Its well-defined structure grants it distinctive physical, chemical, and biological properties and has been widely used for preparing high-performance materials. Recently, click chemistry has enabled the synthesis of various functional POSS-based materials for diverse biomedical applications. This article reviews the recent applications of POSS-based materials in the biomedical field, including cancer treatment, tissue engineering, antibacterial use, and biomedical imaging. Representative examples are discussed in detail. Among the various POSS-based applications, cancer treatment and tissue engineering are the most important. Finally, this review presents the current limitations of POSS-based materials and provides guidance for future research.

Supramolecular nanoparticle loaded with bilirubin enhances cartilage protection and alleviates osteoarthritis via modulating oxidative stress and inflammatory responses.

Osteoarthritis (OA) is a chronic inflammation that gradually leads to cartilage degradation. Prolonged chondrocyte oxidative stress contributes to the development of diseases, including chondrocyte apoptosis, cartilage matrix degradation, and aggravation of articular cartilage damage. Bilirubin (BR) possesses strong antioxidant properties by scavenging reactive oxygen species (ROS) and potent protection effects against inflammation. However, its insolubility and short half-life limit its clinical use. Therefore, we developed a supramolecular system of ε-polylysine (EPL) conjugated by ß-cyclodextrin (ß-CD) on the side chain, and bilirubin was loaded via host-guest interactions, which resulted in the self-assemble of this system into bilirubin-loaded polylysine-ß-cyclodextrin nanoparticle (PB) with improving solubility while reducing toxicity and prolonging medication action time. To explore PB's potential pharmacological mechanisms on OA, we established in vitro and in vivo OA models. PB exerted ROS-scavenging proficiency and anti-apoptotic effects on rat chondrocytes by activating the Nrf2-HO-1/GPX4 signaling pathway. Additionally, PB reprogrammed the cartilage microenvironment by regulating the NF-κB signaling pathway to maintain chondrocyte function. Animal experiments further confirmed that PB had excellent scavenging ability for ROS and inflammatory factors related to charge adsorption with cartilage as well as long retention ability. Together, this work suggests that PB has superior protective abilities with beneficial effects on OA, indicating its great potential for intervention therapy targeting chondrocytes.

MYOCD and SRF-mediated MLCK transcription prevents polymorphonuclear neutrophils from ferroptosis in sepsis-related acute lung injury.

Persistent activation of polymorphonuclear neutrophils (PMNs) plays a crucial role in the development of sepsis-related acute lung injury (ALI). This study investigated key molecular mechanisms involved in the hyperactivation of PMNs during ALI. A mouse model of sepsis-related ALI was generated by lipopolysaccharide (LPS) injection. RNA sequencing identified myosin light chain kinase (MLCK) as the most significant differentially expressed gene (DEG) between PMNs isolated from model and control mice. Myocardin (MYOCD) and serum response factor (SRF) were two of the DEGs that could promote transcription of MLCK by binding to its promoter. Either knockdown of MLCK, MYOCD, or SRF ameliorated dysfunction and edema in the lungs of LPS-treated mice. Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the DEGs are enriched in a ferroptosis-related signaling pathway. The MLCK, MYOCD, or SRF knockdown increased contents of ROS, MDA, ferritin, and ferrous iron, and reduced levels of GSH and GPX4 in the PMNs. However, the MLCK overexpression restored ferroptosis resistance and activity of the PMNs, resulting in increased lung injury. Collectively, this study demonstrates that MYOCD and SRF-mediated MLCK upregulation is correlated with ferroptosis resistance and hyperactivation of PMNs in sepsis-related ALI.

Bioinspired multifunctional cellulose film: In situ bacterial capturing and killing for managing infected wounds.

Bacterial infection of cutaneous wounds can easily lead to occurrence of chronic wounds and even more serious diseases. Therefore, multifunctional, biodegradable, and reusable wound dressings that can quickly manage wound infection and promote wound healing are urgently desired. Herein, inspired by the "capturing and killing" action of Drosera peltata Thunb., a biomimetic cellulose film was constructed to capture the bacteria (via the rough structure of the film) and kill them (via the combination of photodynamic therapy and chemotherapy) to promote wound tissue remodeling. The film (termed OBC-PR) was simply prepared by chemically crosslinking the oxidized bacterial cellulose (OBC) with polyhexamethylene guanidine hydrochloride (PHGH) and rose bengal (RB). Notably, it could effectively capture Escherichia coli and Staphylococcus aureus bacterial cells with capture efficiencies of ∼99 % and ∼96 %, respectively, within 10 min. Furthermore, the in vivo experiments showed that OBC-PR could effectively promote the macrophage polarization toward the M2 phenotype and adequately induce the reconstruction of blood vessels and nerves, thus promoting wound healing. This study provides a potential direction for designing multifunctional wound dressings for managing infected skin wounds in the future.

Carbon-Dots-Mediated Improvement of Antimicrobial Activity of Natural Products.

The development of new microbicidal compounds has become a top priority due to the emergence and spread of drug-resistant pathogenic microbes. In this study, blue-emitting and positively charged carbon dots (CDs), called Du-CDs, were fabricated for the first time utilizing the natural product extract of endophyte Diaporthe unshiuensis YSP3 as raw material through a one-step solvothermal method, which possessed varied functional groups including amino, carboxyl, hydroxyl, and sulfite groups. Interestingly, Du-CDs exhibited notably enhanced antimicrobial activities toward both bacteria and fungi as compared to the natural product extract of YSP3, with low minimum inhibitory concentrations. Moreover, Du-CDs significantly inhibited the formation of biofilms. Du-CDs bound with the microbial cell surface via electronic interaction or hydrophobic interaction entered the microbial cells and were distributed fully inside the cells. Du-CDs caused cell membrane damage and/or cell division cycle interruption, resulting in microbial cell death. Moreover, Du-CDs exhibited an improved antimicrobial effect and accelerated wound healing ability with good biocompatibility in the mouse model. Overall, we demonstrate that the formation of CDs from fungal natural products presents a promising and potential means to develop novel antimicrobial agents with great fluorescence, improved microbiocidal effect and wound healing capacity, and good biosafety for combating microbial infections.

Multifunctional Near-Infrared Phosphors Cr3+/Ni2+ Codoped Mg3Ga2GeO8 Based on Energy Transfer from Cr3+ to Ni2.

Currently, near-infrared (NIR) light-emitting materials have been widely used in many fields, such as night vision, bioimaging, and nondestructive analysis. However, it is difficult to achieve multifunction in certain NIR light emitting phosphor. Herein, we propose a new near-infrared phosphor Mg3Ga2GeO8:Cr3+,Ni2+ that can be applied to at least three fields, i.e., identification of compounds, temperature sensing, anticounterfeiting, and other applications. The multifunctional material exhibited efficient broadband emission of 650-1650 nm under 420 nm excitation. The emission intensity of Ni2+ in Mg3Ga2GeO8:Cr3+,Ni2+ is enhanced by two times compared with that of Ni2+ in Mg3Ga2GeO8:Ni2+ due to the energy transfer process. Compared with phosphor single doped with Ni2+, Mg3Ga2GeO8:Cr3+,Ni2+ is more convincing in organic compound recognition because it is based on two emission bands: 600-1100 nm and 1100-1650 nm. As a temperature sensor, Mg3Ga2GeO8:Cr3+,Ni2+ is an ideal temperature-sensing material. This work not only provides a super broadband NIR emitting phosphor with multiple functions but also presents a practical approach for the development of high-efficiency and multifunctional NIR phosphors.

Enhancing oocyte in vitro maturation and quality by melatonin/bilirubin cationic nanoparticles: A promising strategy for assisted reproduction techniques.

In assisted reproduction techniques, oocytes encounter elevated levels of reactive oxygen species (ROS) during in vitro maturation (IVM). Oxidative stress adversely affects oocyte quality, hampering their maturation, growth, and subsequent development. Thus, mitigating excessive ROS to safeguard less viable oocytes during IVM stands as a viable strategy. Numerous antioxidants have been explored for oocyte IVM, yielding considerable effects; however, several aspects, including solubility, stability, and safety, demand attention and resolution. In this study, we developed nanoparticles by self-assembling endogenous bilirubin and melatonin hormone coated with bilirubin-conjugated glycol chitosan (MB@GBn) to alleviate oxidative stress and enhance oocyte maturation. The optimized MB@GBn exhibited a uniform spherical shape, measuring 128 nm in particle size, with a PDI value of 0.1807 and a surface potential of +11.35 mV. The positively charged potential facilitated nanoparticle adherence to the oocyte surface through electrostatic interaction, allowing for functional action. In vitro studies demonstrated that MB@GB significantly enhanced the maturation of compromised oocytes. Further investigation revealed MB@GB's effectiveness in scavenging ROS, reducing intracellular calcium levels, and suppressing mitochondrial polarization. This study not only offers a novel perspective on nano drug delivery systems for biomedical applications but also presents an innovative strategy for enhancing oocyte IVM.

Hyperbaric oxygen enhances tumor penetration and accumulation of engineered bacteria for synergistic photothermal immunotherapy.

Bacteria-mediated cancer therapeutic strategies have attracted increasing interest due to their intrinsic tumor tropism. However, bacteria-based drugs face several challenges including the large size of bacteria and dense extracellular matrix, limiting their intratumoral delivery efficiency. In this study, we find that hyperbaric oxygen (HBO), a noninvasive therapeutic method, can effectively deplete the dense extracellular matrix and thus enhance the bacterial accumulation within tumors. Inspired by this finding, we modify Escherichia coli Nissle 1917 (EcN) with cypate molecules to yield EcN-cypate for photothermal therapy, which can subsequently induce immunogenic cell death (ICD). Importantly, HBO treatment significantly increases the intratumoral accumulation of EcN-cypate and facilitates the intratumoral infiltration of immune cells to realize desirable tumor eradication through photothermal therapy and ICD-induced immunotherapy. Our work provides a facile and noninvasive strategy to enhance the intratumoral delivery efficiency of natural/engineered bacteria, and may promote the clinical translation of bacteria-mediated synergistic cancer therapy.

A red blood cell-derived bionic microrobot capable of hierarchically adapting to five critical stages in systemic drug delivery.

The tumour-targeting efficiency of systemically delivered chemodrugs largely dictates the therapeutic outcome of anticancer treatment. Major challenges lie in the complexity of diverse biological barriers that drug delivery systems must hierarchically overcome to reach their cellular/subcellular targets. Herein, an "all-in-one" red blood cell (RBC)-derived microrobot that can hierarchically adapt to five critical stages during systemic drug delivery, that is, circulation, accumulation, release, extravasation, and penetration, is developed. The microrobots behave like natural RBCs in blood circulation, due to their almost identical surface properties, but can be magnetically manipulated to accumulate at regions of interest such as tumours. Next, the microrobots are "immolated" under laser irradiation to release their therapeutic cargoes and, by generating heat, to enhance drug extravasation through vascular barriers. As a coloaded agent, pirfenidone (PFD) can inhibit the formation of extracellular matrix and increase the penetration depth of chemodrugs in the solid tumour. It is demonstrated that this system effectively suppresses both primary and metastatic tumours in mouse models without evident side effects, and may represent a new class of intelligent biomimicking robots for biomedical applications.

Iodine/soluble starch cryogel: An iodine-based antiseptic with instant water-solubility, improved stability, and potent bactericidal activity.

Iodine (I2) as a broad-spectrum antiseptic has been widely used for treating bacterial infections. However, I2 has low water-solubility and sublimes under ambient conditions, which limits its practical antibacterial applications. The highly specific and sensitive reaction between I2 and starch discovered 200 years ago has been extensively applied in analytical chemistry, but the antibacterial activity of the I2-starch complex is rarely investigated. Herein, we develop a novel type of iodine-based antiseptics, iodine-soluble starch (I2-SS) cryogel, which can dissolve in water instantly and almost completely kill bacteria in 10 min at 2 µg/mL of I2. Although KI3 and the commercially available povidone­iodine (I2-PVP) solutions show similar antibacterial efficacy, the high affinity of I2 to SS largely enhances the shelf stability of the I2-SS solution with ∼73 % I2 left after one-week storage at room temperature. In sharp contrast, ∼8.5 % and âˆ¼2.5 % I2 are detected in KI3 and I2-PVP solutions, respectively. Mechanistic study reveals that the potent antibacterial effect of I2-SS originates from its attack on multiple bacterial targets. The outstanding antibacterial activity, capability of accelerating wound healing, and good biocompatibility of I2-SS are verified through further in vivo experiments. This work may promote the development of next-generation iodine-based antiseptics for clinical use.

Fluorescent carbon dots for discriminating cell types: a review.

Carbon dots (CDs) are quasi-spherical carbon nanoparticles with excellent photoluminescence, good biocompatibility, favorable photostability, and easily modifiable surfaces. CDs, serving as fluorescent probes, have emerged as an ideal tool for cellular differentiation owing to their outstanding luminescence performance and tunable surface properties. In this review, we summarize the recent research progress with CDs in the differentiation of cancer/normal cells, Gram-positive/Gram-negative bacteria, and live/dead cells, as well as the cellular differences used for differentiation. Additionally, we summarize the preparation methods, raw materials, and properties of the CDs used for cell discrimination. The differentiation mechanisms and the advantages or limitations of the differentiation methods are also introduced. Finally, we propose several research challenges in this field and future research directions that require extensive investigation. It is hoped that this review will help researchers in the design of new CDs as ideal fluorescent probes for realizing diverse cell differentiation applications.

Russell Mechanism-Mediated Cancer Therapy: A Minireview.

The Russell mechanism, proposed by Russell, is a cyclic mechanism for the formation of linear tetroxide intermediates, which can spontaneously produce cytotoxic singlet oxygen (1O2) independent of oxygen, suggesting its anticancer potential. Compared with other mainstream anticancer strategies, the Russell mechanism employed for killing cancer cells does not require external energy input, harsh pH condition, and sufficient oxygen. However, up till now, the applications of Russell mechanism in antitumor therapy have been relatively rare, and there is almost no summary of the Russell mechanism in the cancer therapy field. This minireview introduces the different metal elements-based Russell mechanisms and the relevant research progress in Russell mechanism-based cancer therapy in recent years. At the same time, we briefly discussed the current challenges and future development regarding the applications of Russell mechanism. It is hoped that this review can further expand the research of Russell Mechanism in the biomedical field, and inspire researchers to extend its application fields to antibacterial, antiinflammatory, and wound healing uses.

In Situ Construction of Elastic Solid-State Polymer Electrolyte with Fast Ionic Transport for Dendrite-Free Solid-State Lithium Metal Batteries.

Solid-state lithium metal batteries (LMBs) have been extensively investigated owing to their safer and higher energy density. In this work, we prepared a novel elastic solid-state polymer electrolyte based on an in situ-formed elastomer polymer matrix with ion-conductive plasticizer crystal embedded with Li6.5La3Zr1.5Ta0.5O12 (LLZTO) nanoparticles, denoted as LZT/SN-SPE. The unique structure of LZT/SN-SPE shows excellent elasticity and flexibility, good electrochemical oxidation tolerance, high ionic conductivity, and high Li+ transference number. The role of LLZTO filler in suppressing the side reactions between succinonitrile (SN) and the lithium metal anode and propelling the Li+ diffusion kinetics can be affirmed. The Li symmetric cells with LZT/SN-SPE cycled stably over 1100 h under a current density of 5 mA cm-2, and Li||LiFePO4 cells realized an excellent rate (92.40 mAh g-1 at 5 C) and long-term cycling performance (98.6% retention after 420 cycles at 1 C). Hence, it can provide a promising strategy for achieving high energy density solid-state LMBs.

Multifunctional iron-apigenin nanocomplex conducting photothermal therapy and triggering augmented immune response for triple negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of ß-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment.

Ultrabright Green-Emissive Nanodots for Precise Biological Visualization.

Developing general methods to fabricate water-dispersible and biocompatible fluorescent probes will promote different biological visualization applications. Herein, we report a metal-facilitated method to fabricate ultrabright green-emissive nanodots via the one-step solvothermal treatment of rose bengal, ethanol, and various metal ions. These metal-doped nanodots show good water dispersity, ultrahigh photoluminescence quantum yields (PLQYs) (e.g., the PLQY of Fe-doped nanodots (FeNDs) was ∼97%), and low phototoxicity. Owing to the coordination effect of metal ions, the FeNDs realize glutathione detection with outstanding properties. Benefiting from the high endoplasmic reticulum (ER) affinity of the chloride group, the FeNDs can act as an ER tracker with long ER imaging capacity (FeNDs: >24 h; commercial ER tracker: ∼1 h) and superb photostability and can achieve tissue visualization in living Caenorhabditis elegans. The metal-doped nanodots represent a general nanodot preparation method and may shed new light on diverse biological visualization uses.

Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

Intestinal Delivery of Probiotics: Materials, Strategies, and Applications.

Probiotics with diverse and crucial properties and functions have attracted broad interest from many researchers, who adopt intestinal delivery of probiotics to modulate the gut microbiota. However, the major problems faced for the therapeutic applications of probiotics are the viability and colonization of probiotics during their processing, oral intake, and subsequent delivery to the gut. The challenges of simple oral delivery (stability, controllability, targeting, etc.) have greatly limited the use of probiotics in clinical therapies. Nanotechnology can endow the probiotics to be delivered to the intestine with improved survival rate and increased resistance to the adverse environment. Additionally, the progress in synthetic biology has created new opportunities for efficiently and purposefully designing and manipulating the probiotics. In this article, a brief overview of the types of probiotics for intestinal delivery, the current progress of different probiotic encapsulation strategies, including the chemical, physical, and genetic strategies and their combinations, and the emerging single-cell encapsulation strategies using nanocoating methods, is presented. The action mechanisms of probiotics that are responsible for eliciting beneficial effects are also briefly discussed. Finally, the therapeutic applications of engineered probiotics are discussed, and the future trends toward developing engineered probiotics with advanced features and improved health benefits are proposed.

A ferroptosis-reinforced nanocatalyst enhances chemodynamic therapy through dual H2O2 production and oxidative stress amplification.

The existence of a delicate redox balance in tumors usually leads to cancer treatment failure. Breaking redox homeostasis by amplifying oxidative stress and reducing glutathione (GSH) can accelerate cancer cell death. Herein, we construct a ferroptosis-reinforced nanocatalyst (denoted as HBGL) to amplify intracellular oxidative stress via dual H2O2 production-assisted chemodynamic therapy (CDT). Specifically, a long-circulating liposome is employed to deliver hemin (a natural iron-containing substrate for Fenton reaction and ferroptosis), ß-lapachone (a DNA topoisomerase inhibitor with H2O2 generation capacity for chemotherapy), and glucose oxidase (which can consume glucose for starvation therapy and generate H2O2). HBGL can achieve rapid, continuous, and massive H2O2 and •OH production and GSH depletion in cancer cells, resulting in increased intracellular oxidative stress. Additionally, hemin can reinforce the ferroptosis-inducing ability of HBGL, which is reflected in the downregulation of glutathione peroxidase-4 and the accumulation of lipid peroxide. Notably, HBGL can disrupt endo/lysosomes and impair mitochondrial function in cancer cells. HBGL exhibits effective tumor-killing ability without eliciting obvious side effects, indicating its clinical translation potential for synergistic starvation therapy, chemotherapy, ferroptosis therapy, and CDT. Overall, this nanocatalytic liposome may be a promising candidate for achieving potentiated cancer treatment.

Thrombin and Thrombin-Incorporated Biomaterials for Disease Treatments.

Thrombin, a coagulation-inducing protease, has long been used in the hemostatic field. During the past decades, many other therapeutic uses of thrombin have been developed. For instance, burn treatment, pseudoaneurysm therapy, wound management, and tumor vascular infarction (or tumor vasculature blockade therapy) can all utilize the unique and powerful function of thrombin. Based on their therapeutic effects, many thrombin-associated products have been certificated by the Food and Drug Administration, including bovine thrombin, human thrombin, recombinant thrombin, fibrin glue, etc. Besides, several thrombin-based drugs are currently undergoing clinical trials. In this article, the therapeutic uses of thrombin (from the initial hemostasis to the latest cancer therapy), the commercially available drugs associated with thrombin, and the pros and cons of thrombin-based therapeutics (e.g., adverse immune responses related to bovine thrombin, thromboinflammation, and vasculogenic "rebounds") are summarized. Further, the current challenges and possible future research directions of thrombin-incorporated biomaterials and therapies are discussed. It is hoped that this review may provide a valuable reference for researchers in this field and help them to design safer and more effective thrombin-based drugs for fighting against various intractable diseases.