Softening the tumor matrix through cholesterol depletion breaks the physical barrier for enhanced antitumor therapy.

The tumor develops defense tactics, including conversing the mechanical characteristics of tumor cells and their surrounding environment. A recent study reported that cholesterol depletion stiffens tumor cells, which could enhance adaptive T-cell immunotherapy. However, it remains unclear whether reducing the cholesterol in tumor cells contributes to re-educating the stiff tumor matrix, which serves as a physical barrier against drug penetration. Herein, we found that depleting cholesterol from tumor cells can demolish the intratumor physical barrier by disrupting the mechanical signal transduction between tumor cells and the extracellular matrix through the destruction of lipid rafts. This disruption allows nanoparticles (H/S@hNP) to penetrate deeply, resulting in improved photodynamic treatment. Our research also indicates that cholesterol depletion can inhibit the epithelial-mesenchymal transition and repolarize tumor-associated macrophages from M2 to M1, demonstrating the essential role of cholesterol in tumor progression. Overall, this study reveals that a cholesterol-depleted, softened tumor matrix reduces the difficulty of drug penetration, leading to enhanced antitumor therapeutics.

Biodegradable and Efficient Charge-Migrated Z-Scheme Heterojunction Amplifies Cancer Ferroptosis by Blocking Defensive Redox System.

Ferroptosis is an emerging non-apoptotic death process, mainly involving lipid peroxidation (LPO) caused by iron accumulation, which is potentially lethal to the intrinsically apoptotic-resistant malignant tumor. However, it is still restricted by the inherent antioxidant systems of tumor cells and the poor efficacy of traditional iron-based ferroptosis initiators. Herein, the study develops a novel ferroptosis-inducing agent based on PEGylated Cu+/Cu2+-doped black phosphorus@polypyrrole heterojunction (BP@CPP), which is constructed by utilizing the phosphate on the surface of BP to chelate Cu ions and initiating subsequent in situ polymerization of pyrrole. As a novel Z-scheme heterojunction, BP@CPP possesses an excellent photocatalytic activity in which the separated electron-hole pairs under laser irradiation endow it with powerful oxidizing and reducing capacities, which synergy with Cu+/Cu2+ self-cycling catalyzing Fenton-like reaction to further strengthen reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, ultimately leading to efficient ferroptosis. Systematic in vitro and in vivo evaluations demonstrate that BP@CPP effectively inhibit tumor growth by inducing desired ferroptosis while maintaining a favorable biosafety in the body. Therefore, the developed BP@CPP-based ferroptosis initiator provides a promising strategy for ferroptosis-like cancer therapy.

Human-Hair-Derived Natural Particles as Multifunctional Sunscreen for Effective UV Protection.

Excessive ultraviolet (UV) radiation can lead to a series of skin problems. Although commercial sunscreens can protect skin from UV-induced damage to an extent, the side effects caused by such products are still worrisome. Here, inspired by the natural photoprotection effect of human hair, we extracted the multifunctional particles from human hair as sunscreens for UV protection. Both in vitro and in vivo results indicate that hair-derived particles (HDPs) could effectively protect skin from UV radiation. Besides, HDPs retain the antioxidant capability of melanin in hair, which avoids UV-induced oxidative damage. In addition, the unique shape of HDPs can prevent them from penetrating into the skin, thus avoiding potential toxicity. Moreover, owing to their mesoporous structure, the particles can also be used as drug carriers. With the loading of octocrylene, the particles are more effective in blocking UV radiation. This study provides an ingenious tactic for the design and development of sunscreens from a natural substance.

Construction of Zn-doped RuO2 nanowires for efficient and stable water oxidation in acidic media.

Oxygen evolution reaction catalysts capable of working efficiently in acidic media are highly demanded for the commercialization of proton exchange membrane water electrolysis. Herein, we report a Zn-doped RuO2 nanowire array electrocatalyst with outstanding catalytic performance for the oxygen evolution reaction under acidic conditions. Overpotentials as low as 173, 304, and 373 mV are achieved at 10, 500, and 1000 mA cm-2, respectively, with robust stability reaching to 1000 h at 10 mA cm-2. Experimental and theoretical investigations establish a clear synergistic effect of Zn dopants and oxygen vacancies on regulating the binding configurations of oxygenated adsorbates on the active centers, which then enables an alternative Ru-Zn dual-site oxide path of the reaction. Due to the change of reaction pathways, the energy barrier of rate-determining step is reduced, and the over-oxidation of Ru active sites is alleviated. As a result, the catalytic activity and stability are significantly enhanced.

Peptide-based siRNA delivery system for tumor vascular normalization and gene silencing in 4T1 cells.

Efficient gene delivery in an integrated drug delivery system is urgent for multimodal antitumor therapy. Herein, we describe a protocol for constructing a peptide-based siRNA delivery system to achieve tumor vascular normalization and gene silencing in 4T1 cells. We highlighted four major steps, including (1) synthesis of the chimeric peptide, (2) preparation and characterization of PA7R@siRNA micelleplexes, (3) in vitro tube formation assay and transwell cell migration assay, and (4) siRNA transfection in 4T1 cells. This delivery system is expected to be used to silence gene expression, normalize tumor vasculature, and perform other treatments based on the different peptide segments. For complete details on the use and execution of this protocol, please refer to Yi et al. (2022).1.

Vaccine-like nanomedicine for cancer immunotherapy.

The successful clinical application of immune checkpoint blockade (ICB) and chimeric antigen receptor T cells (CAR-T) therapeutics has attracted extensive attention to immunotherapy, however, their drawbacks such as limited specificity, persistence and toxicity haven't met the high expectations on efficient cancer treatments. Therapeutic cancer vaccines which instruct the immune system to capture tumor specific antigens, generate long-term immune memory and specifically eliminate cancer cells gradually become the most promising strategies to eradicate tumor. However, the disadvantages of some existing vaccines such as weak immunogenicity and in vivo instability have restricted their development. Nanotechnology has been recently incorporated into vaccine fabrication and exhibited promising results for cancer immunotherapy. Nanoparticles promote the stability of vaccines, as well as enhance antigen recognition and presentation owing to their nanometer size which promotes internalization of antigens by phagocytic cells. The surface modification with targeting units further permits the delivery of vaccines to specific cells. Meanwhile, nanocarriers with adjuvant effect can improve the efficacy of vaccines. In addition to classic vaccines composed of antigens and adjuvants, the nanoparticle-mediated chemotherapy, radiotherapy and certain other therapeutics could induce the release of tumor antigens in situ, which therefore effectively simulate antitumor immune responses. Such vaccine-like nanomedicine not only kills primary tumors, but also prevents tumor recurrence and helps eliminate metastatic tumors. Herein, we introduce recent developments in nanoparticle-based delivery systems for antigen delivery and in situ antitumor vaccination. We will also discuss the remaining opportunities and challenges of nanovaccine in clinical translation towards cancer treatment.

Biodegradable calcium sulfide-based nanomodulators for H2S-boosted Ca2+-involved synergistic cascade cancer therapy.

Hydrogen sulfide (H2S) is the most recently discovered gasotransmitter molecule that activates multiple intracellular signaling pathways and exerts concentration-dependent antitumor effect by interfering with mitochondrial respiration and inhibiting cellular ATP generation. Inspired by the fact that H2S can also serve as a promoter for intracellular Ca2+ influx, tumor-specific nanomodulators (I-CaS@PP) have been constructed by encapsulating calcium sulfide (CaS) and indocyanine green (ICG) into methoxy poly (ethylene glycol)-b-poly (lactide-co-glycolide) (PLGA-PEG). I-CaS@PP can achieve tumor-specific biodegradability with high biocompatibility and pH-responsive H2S release. The released H2S can effectively suppress the catalase (CAT) activity and synergize with released Ca2+ to facilitate abnormal Ca2+ retention in cells, thus leading to mitochondria destruction and amplification of oxidative stress. Mitochondrial dysfunction further contributes to blocking ATP synthesis and downregulating heat shock proteins (HSPs) expression, which is beneficial to overcome the heat endurance of tumor cells and strengthen ICG-induced photothermal performance. Such a H2S-boosted Ca2+-involved tumor-specific therapy exhibits highly effective tumor inhibition effect with almost complete elimination within 14-day treatment, indicating the great prospect of CaS-based nanomodulators as antitumor therapeutics.

Isoginkgetin synergizes with doxorubicin for robust co-delivery to induce autophagic cell death in hepatocellular carcinoma.

Doxorubicin (DOX) widely used in hepatocellular carcinoma (HCC) can induce serious side effects and drug resistance. Herein, we aimed to seek a strategy to improve the efficacy and reduce the side effects of DOX in HCC based on an autophagy inducer drug called isoginkgetin (ISO). The design of multifunctional nanocarriers based on hyaluronic acid-conjugated and manganese-doped mesoporous silica nanoparticles (HM) for the co-delivery of antitumor drugs against HCC provided an effective and promising antitumor strategy. Our results showed that HM@ISO@DOX could efficiently inhibit HCC cell proliferation through activating autophagy through AMPKa-ULK1 pathway. Moreover, intravenous injection of HM@ISO@DOX significantly suppressed HCC tumor progression in nude mouse HCC model. Collectively, our findings revealed an anti-HCC mechanism of HM@ISO@DOX through autophagy and provide an effective therapeutic strategy for HCC. STATEMENT OF SIGNIFICANCE: In our study, we constructed a co-delivery system by loading ISO and DOX in the mesoporous channels of manganese-doped mesoporous silica nanoparticles, which could be further conjugated with hyaluronic acid to obtain HM@ISO@DOX. The nanocarriers had been demonstrated to be biodegradable under the acidic and reducing tumor microenvironment, as well as to possess the tumor targeting capability via the conjugated hyaluronic acid. In addition, HM@ISO@DOX enhanced the therapeutic efficacy against human HCC tumor through the combinatorial therapies of chemotherapeutics, Mn2+-mediated chemodynamic therapeutics and autophagic cell death, which might be achieved through AMPK-ULK1 signaling. This work revealed that such a nanomedicine exhibited superior tumor accumulation and antitumor efficiency against HCC with extremely low systemic toxicity in an autophagy-boosted manner.

Polypyrrole Nanoenzymes as Tumor Microenvironment Modulators to Reprogram Macrophage and Potentiate Immunotherapy.

Nanozyme-based tumor catalytic therapy has attracted widespread attention in recent years, but its therapeutic outcome is drastically diminished by species of nanozyme, concentration of substrate, pH value, and reaction temperature, etc. Herein, a novel Cu-doped polypyrrole nanozyme (CuP) with trienzyme-like activities, including catalase (CAT), glutathione peroxidase (GPx), and peroxidase (POD), is first proposed by a straightforward one-step procedure, which can specifically promote O2 and ·OH elevation but glutathione (GSH) reduction in tumor microenvironment (TME), causing irreversible oxidative stress damage to tumor cells and reversing the redox balance. The PEGylated CuP nanozyme (CuPP) has been demonstrated to efficiently reverse immunosuppressive TME by overcoming tumor hypoxia and re-educating macrophage from pro-tumoral M2 to anti-tumoral M1 phenotype. More importantly, CuPP exhibits hyperthermia-enhanced enzyme-mimic catalytic and immunoregulatory activities, which results in intense immune responses and almost complete tumor inhibition by further combining with αPD-L1. This work opens intriguing perspectives not only in enzyme-catalytic nanomedicine but also in macrophage-based tumor immunotherapy.

Oxidative stress-amplified nanomedicine for intensified ferroptosis-apoptosis combined tumor therapy.

Ferroptosis, as an effective sensitizer for apoptosis-based cancer treatments, has been elucidated to rely on high levels of intracellular oxidative stress mediated by the accumulation of reactive oxygen species (ROS). However, ferroptosis-related oxidation effect is largely counteracted by the endogenous reductive glutathione (GSH). Here, we constructed a self-assembled metal-organic nanomedicine p53/Ce6@ZF-T, which was composed of p53 plasmid-complexed chlorin e6 (Ce6)-poly(amidoamine), Fe2+-containing mesoporous zeolitic imidazolate framework-8 and naturally derived tannic acid (TA). The highly cytotoxic ROS was continuously produced via Fe2+-mediated and TA-assisted enhanced Fenton reaction as well as Ce6-induced photosensitive reaction, and meanwhile, the intratumoral upregulated p53 expression inactivated glutathione peroxidase 4 (GPX4) to suppress lipid peroxidation (LPO) resistance, thus resulting in amplified oxidative stress and intensified ferroptosis-apoptosis therapy. The notable anticancer efficacy of p53/Ce6@ZF-T both in vitro and in vivo substantially evidenced the high feasibility of oxidative stress-amplified therapeutic modality for enhanced ferroptosis-apoptosis combined therapy, which would be a promising approach in the field of cancer treatment in the future.

ATP-exhausted nanocomplexes for intratumoral metabolic intervention and photoimmunotherapy.

Tumor cells reprogram the metabolic pathways to acquire abundant nutrients and sustain malignant proliferation. This fierce metabolic competition in tumor ecosystem has been uncovered to be associated with tumor microenvironmental immunosuppression. Here we develop an adenosine triphosphate (ATP)-exhausted nanocomplex (IR@ZIF-RGD) to intervene in tumor energy metabolism and regulate tumor immune microenvironment. IR@ZIF-RGD could effectively deplete intracellular ATP and inhibit ATP synthesis by ATP-responsive ZIF-90 and siRNA targeting thioredoxin reductase-2, respectively, thus leading to tumor metabolism disorders and immunosuppressive reversion. Meanwhile, IR@ZIF-RGD induced oxidative stress and ICG triggered photothermal therapy could provoke potent immunogenic cell death to enhance antitumor immunogenicity. Such a photo-immunometabolic nanocomplex has been demonstrated to be an efficient vaccine to elicit protective anticancer immune response in vivo, achieving suppressed growth of both primary and abscopal tumors, as well as inhibited tumor metastasis.

A New Criterion for Exponential Stability of a Class of Hopfield Neural Network with Time-Varying Delay Based on Gronwall's Inequality.

In this paper, we study the problem of exponential stability for the Hopfield neural network with time-varying delays. Different from the existing results, we establish new stability criteria by employing the method of variation of constants and Gronwall's integral inequality. Finally, we give several examples to show the effectiveness and applicability of the obtained criterion.

Tumor Microenvironment-Specific Chemical Internalization for Enhanced Gene Therapy of Metastatic Breast Cancer.

Benefiting from treating diseases at the genetic level, gene therapy has been considered a new revolution in the biomedical field. However, the extracellular and intracellular barriers during gene transport such as enzymatic degradation and endo-/lysosomal sequestration significantly compromise the therapeutic efficacy. Though photochemical internalization (PCI) has emerged as a promising approach for causing endo-/lysosomal leakage with translocation of the internalized molecules into the cytosol, its effect is still unsatisfactory due to the insufficient light penetration depth. Here, we develop tumor microenvironment-specific enhanced gene delivery by means of ROS generated from the in situ cascaded catalytic reactions in tumors involving GOx-mediated redox reaction and Mn2+-mediated Fenton-like reaction. The efficient enzymatic protection and successful endo-/lysosomal escape of cargo gene complexes have been demonstrated. Moreover, anti-Twist siRNA-loaded G@MMSNs-P exhibit tumor-specific biodegradation, excellent T1-weighted MR imaging, and significant inhibitory effects against breast cancer growth and pulmonary metastasis.

Potentiating photodynamic therapy of ICG-loaded nanoparticles by depleting GSH with PEITC.

Photodynamic therapy (PDT) is a clinically approved cancer treatment which utilizes reactive oxygen species (ROS) to eradicate cancer cells. But the high concentration of GSH inside tumor cells can neutralize the generated ROS during PDT, resulting in an insufficient therapeutic effect. To address this issue, we combined ICG-loaded nanoparticles with PEITC for potent PDT. ICG encapsulated in novel hydroxyethyl starch-oleic acid conjugate (HES-OA) nanoparticles (∼50 nm) exhibited excellent stability and efficient singlet oxygen generation under laser irradiation, promoted cellular uptake, and enhanced tumor accumulation, whilst PEITC depleted intracellular GSH significantly. As a result, PDT based on ICG-loaded NPs combined with PEITC synergistically suppressed cancer cells both in vitro and in vivo. Potentiating ICG-loaded NPs with PEITC represents a novel and efficient strategy to enhance PDT efficacy.

TrackCC: A Practical Wireless Indoor Localization System Based on Less-Expensive Chips.

This paper aims at proposing a new wireless indoor localization system (ILS), called TrackCC, based on a commercial type of low-power system-on-chip (SoC), nRF24LE1. This type of chip has only l output power levels and acute fluctuation for a received minimum power level in operation, which give rise to many practical challenges for designing localization algorithms. In order to address these challenges, we exploit the Markov theory to construct a ( l + 1 ) × ( l + 1 ) -sized state transition matrix to remove the fluctuation, and then propose a priority-based pattern matching algorithm to search for the most similar match in the signal map to estimate the real position of unknown nodes. The experimental results show that, compared to two existing wireless ILSs, LANDMARC and SAIL, which have meter level positioning accuracy, the proposed TrackCC can achieve the decimeter level accuracy on average in both line-of-sight (LOS) and non-line-of-sight (NLOS) senarios.