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Weight loss by increasing energy consumption of thermogenic adipocytes to overcome obesity remains a challenge. Herein, we established a transdermal device that was based on the local and temporarily controlled delivery of succinate (SC), a tricarboxylic acid cycle metabolic intermediate to stimulate the thermogenesis pathway of uncoupling protein 1 (UCP1) and accelerate energy dissipation of brown adipose tissue (BAT) under the dorsal interscapular skin, further initiating the consumption of fatty acids by systemic metabolism. SC microneedle patches significantly suppressed weight gain and fat accumulation of remote organs, including liver and peripheral white adipose tissue (WAT) in high-fat diet-induced obese mice. mRNA expression levels of

A major challenge in the use of chemotherapy and immunotherapy is hypoxia-induced progression of tumor cells. We aim to curb hypoxia using metal-based O

In living systems, non‐equilibrium states that control the assembly‐disassembly of cellular components underlie the gradual complexification of life, whereas in nonliving systems, most molecules follow the laws of thermodynamic equilibrium to sustain dynamic consistency. Little is known about the roles of non‐equilibrium states of interactions between supramolecules in living systems. Here, a non‐equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aβ42, an aggregate‐prone protein that causes Alzheimer's disease (AD), was identified. Structurally, Aβ42 presents a specific groove that is recognized by the amphiphilicity of LPS bait in a non‐equilibrium manner. Functionally, the transient complex elicits a cellular response to clear extracellular Aβ42 deposits in neuronal cells. Since the impaired clearance of toxic Aβ42 deposits correlates with AD pathology, the non‐equilibrium LPS and Aβ42 could represent a useful target for developing AD therapeutics., Here, a non‐equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aβ42, an aggregate‐prone protein that causes Alzheimer's disease (AD), was identified. Oscillation of the non‐equilibrium state for co‐assembly and clearance of Aβ42 is triggered through the use of a supramolecular bait. Since the impaired clearance of toxic Aβ42 deposits correlates with AD pathology, the LPS and Aβ42 non‐equilibrium could represent a useful target for developing AD therapeutics.

When gold nanoparticles (AuNPs) become extremely small (2 nm in diameter) as gold nanoclusters (AuNCs), an intriguing issue is whether the interactions of free radicals with AuNCs would be essentially different at sufficiently small size. Herein, we report for the first time that the fluorescence of a polyamidoamine (PAMAM) dendrimer-entrapped Au

The progress of wound regeneration relies on inflammation management, while neovascular angiogenesis is a critical aspect of wound healing. In this study, the bioactive core and corona synergism of quantized gold (QG) were developed to simultaneously address these complicated issues, combining the abilities to eliminate endotoxins and provide oxygen. The QG was constructed from ultrasmall nanogold and a loosely packed amine-based corona via a simple process, but it could nonetheless eliminate endotoxins (a vital factor in inflammation also called lipopolysaccharides) and provide oxygen in situ for the remodeling of wound sites. Even while capturing endotoxins through electrostatic interactions, the catalytic active sites inside the nanogold could maintain its surface accessibility to automatically transform the overexpressed hydrogen peroxide in hypoxic wound regions into oxygen. Since the inflammatory stage is an essential stage of wound healing, the provision of endotoxin clearance by the outer organic corona of the QG could slow inflammation in a way that subsequently promoted two other important stages of wound bed healing, namely proliferation and remodeling. Relatedly, the efficacy of two forms of the QG, a liquid form and a dressing form, was demonstrated at wound sites in this study, with both forms promoting the development of granulation, including angiogenesis and collagen deposition. Thus, the simply fabricated dual function nanocomposite presented herein not only offers reduced batch-to-batch variation but also increased options for homecare treatments.

A strong interaction between colistin, a last‐resort antibiotic of the polymyxin family, and free lipopolysaccharide (LPS, also referred to as endotoxin), released from the Gram‐negative bacterial (GNB) outer membrane (OM), has been identified that can decrease the antibacterial efficacy of colistin, potentially increasing the dose of this antibiotic required for treatment. The competition between LPS in the GNB OM and free LPS for the interaction with colistin was prevented by using a supramolecular trap to capture free LPS. The supramolecular trap, fabricated from a subnanometer gold nanosheet with methyl motifs (SAuM), blocks lipid A, preventing the interaction between lipid A and colistin. This can minimize endotoxemia and maximize the antibacterial efficacy of colistin, enabling colistin to be used at lower doses. Thus, the potential crisis of colistin resistance could be avoided., Caught in a trap: The antibiotic colistin targets lipopolysaccharide (LPS) in the Gram‐negative bacterial (GNB) membrane. This interaction is disrupted by free LPS released during infection (path a). A methylated gold nanosheet (SAuM) binds to free LPS, preventing free LPS from binding colistin and reducing endotoxemia (path b). This increases the antibacterial efficacy of colistin, decreasing both the required dose and the risk of resistance.

Despite nanoparticulate platinum (nano-Pt) has been validated to be acting as a platinum-based prodrug for anticancer therapy, the key factor in controlling its cytotoxicity remains to be clarified. In this study, it is found that the corrosion susceptibility of nano-Pt can be triggered by inducing the oxidization of superficial Pt atoms, which can kill both cisplatin-sensitive/resistance cancer cells. Direct evidence in the oxidization of superficial Pt atoms is validated to observe the formation of platinum oxides by X-ray absorption spectroscopy. The cytotoxicity is originated from the dissolution of nano-Pt followed by the release of highly toxic Pt ions during the corrosion process. Additionally, the limiting autophagy induction by nano-Pt might prevent cancer cells from acquiring autophagy-related drug resistance. With such advantages, the possibility of further autophagy-related drug resistance could be substantially reduced or even eliminated in cancer cells treated with nano-Pt. Moreover, nano-Pt is demonstrated to kill cisplatin-resistant cancer cells not only by inducing apoptosis but also by inducing necrosis for pro-inflammatory/inflammatory responses. Thus, nano-Pt treatment might bring additional therapeutic benefits by regulating immunological responses in tumor microenvironment. These findings support the idea that utilizing nano-Pt for its cytotoxic effects might potentially benefit patients with cisplatin resistance in clinical chemotherapy.

The cytotoxicity of nanozymes has drawn much attention recently because their peroxidase-like activity can decompose hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) under acidic conditions. Although catalytic activities of nanozymes are highly associated with their surface properties, little is known about the mechanism underlying the surface coating-mediated enzyme-like activities. Herein, it is reported for the first time that amine-terminated PAMAM dendrimer-entrapped gold nanoclusters (AuNCs-NH2 ) unexpectedly lose their peroxidase-like activity while still retaining their catalase-like activity in physiological conditions. Surprisingly, the methylated form of AuNCs-NH2 (i.e., MAuNCs-N(+) R3 , where R = H or CH3 ) results in a dramatic recovery of the intrinsic peroxidase-like activity while blocking most primary and tertiary amines (1°- and 3°-amines) of dendrimers to form quaternary ammonium ions (4°-amines). However, the hidden peroxidase-like activity is also found in hydroxyl-terminated dendrimer-encapsulated AuNCs (AuNCs-OH, inside backbone with 3°-amines), indicating that 3°-amines are dominant in mediating the peroxidase-like activity. The possible mechanism is further confirmed that the enrichment of polymeric 3°-amines on the surface of dendrimer-encapsulated AuNCs provides sufficient suppression of the critical mediator •OH for the peroxidase-like activity. Finally, it is demonstrated that AuNCs-NH2 with diminished cytotoxicity have great potential for use in primary neuronal protection against oxidative damage.

Endotoxicity originating from a dangerous debris (i.e., lipopolysaccharide, LPS) of Gram-negative bacteria is a challenging clinical problem, but no drugs or therapeutic strategies that can successfully address this issue have been identified yet. In this study, we report a subnanometer gold cluster that can efficiently block endotoxin activity to protect against sepsis. The endotoxin blocker consists of a gold nanocluster that serves as a flakelike substrate and a coating of short alkyl motifs that act as an adhesive to dock with LPS by compacting the intramolecular hydrocarbon chain-chain distance ( d-spacing) of lipid A, an endotoxicity active site that can cause overwhelming cytokine induction resulting in sepsis progression. Direct evidence showed the d-spacing values of lipid A to be decreased from 4.19 Å to either 3.85 or 3.54 Å, indicating more dense packing densities in the presence of subnanometer gold clusters. In terms of biological relevance, the concentrations of key pro-inflammatory NF-κB-dependent cytokines, including plasma TNF-α, IL-6, and IL-1β, and CXC chemokines, in LPS-challenged mice showed a noticeable decrease. More importantly, we demonstrated that the treatment of antiendotoxin gold nanoclusters significantly prolonged the survival time in LPS-induced septic mice. The ultrasmall gold nanoclusters could target lipid A of LPS to deactivate endotoxicity by compacting its packing density, which might constitute a potential therapeutic strategy for the early prevention of sepsis caused by Gram-negative bacterial infection.

When gold nanoparticles (AuNPs) become extremely small (

Photodynamic therapy (PDT) typically involves oxygen (O

We report on caged Pt nanoclusters that are able to exert tumor-inside activation for anticancer chemotherapeutics and to minimize systemic toxicity. By shrinking the Pt size to 1 nm, it possesses corrodibility for dissolution in weakly acidic organelles to release toxic Pt ions. The therapeutic effect in exerting tumor-inside activation is confirmed in vivo by post-modifying a pH-cleavable PEG corona and mixing it with a tumor-homing peptide for tumour suppression.

Photodynamic therapy (PDT) typically involves oxygen (O2 ) consumption and therefore suffers from greatly limited anticancer therapeutic efficacy in tumor hypoxia. Here, it is reported for the first time that amine-terminated, PAMAM dendrimer-encapsulated gold nanoclusters (AuNCs-NH2 ) can produce O2 for PDT via their intrinsic catalase-like activity. The AuNCs-NH2 not only show optimum H2 O2 consumption via the catalase-like activity over the physiological pH range (i.e., pH 4.8-7.4), but also extend such activity to acidic conditions. The possible mechanism is deduced from that the enriched tertiary amines of dendrimers are easily protonated in acidic solutions to facilitate the preadsorption of OH on the metal surface, thereby favorably triggering the catalase-like reaction. By taking advantage of the exciting feature on AuNCs-NH2 , the possibility to supply O2 via the catalase-like activity of AuNCs-NH2 for PDT against hypoxia of cancer cells was further studied. This proof-of-concept study provides a simple way to combine current O2 -dependent cancer therapy of PDT to overcome cancer cell hypoxia, thus achieving more effective anticancer treatments.

Biothiols have been reported to involve in intracellular redox-homeostasis against oxidative stress. In this study, a highly selective and sensitive fluorescent probe for sensing biothiols is explored by using an ultrasmall gold nanodot (AuND), the dendrimer-entrapped Au 8 -cluster. This strategy relies upon a thiol/disulfide exchange to trigger the fluorescence change through a photoinduced electron transfer (PET) process between the Au 8 -cluster (as an electron donor) and 2-pyridinethiol (2-PyT) (as an electron acceptor) for sensing biothiols. When 2-PyT is released via the cleavage of disulfide bonds by biothiols, the PET process from the Au 8 -cluster to 2-PyT is initiated, resulting in fluorescence quenching. The fluorescence intensity was found to decrease linearly with glutathione (GSH) concentration (0–1500 μM) at physiological relevant levels and the limit of detection for GSH was 15.4 μM. Compared to most nanoparticle-based fluorescent probes that are limited to detect low molecular weight thiols (LMWTs; i.e., GSH and cysteine), the ultrasmall Au 8 -cluster-based probe exhibited less steric hindrance and can be directly applied in selectively and sensitively detecting both LMWTs and high molecular weight thiols (HMWTs; i.e., protein thiols). Based on such sensing platform, the surface-functionalized Au 8 -cluster has significant promise for use as an efficient nanoprobe for intracellular fluorescence imaging of biothiols including protein thiols in living cells whereas other nanoparticle-based fluorescent probes cannot.

The proof of concept of a simple sensing platform based on the fluorescence of a gold cluster consisting of eight atoms, which is easily manipulated by reduction and oxidation of a specific molecule in the absence of chemical linkers, is demonstrated. Without using any coupling reagents to arrange the distance of the donor-acceptor pair, the fluorescence of the Au(8) -cluster is immediately switched off in the presence of 2-pyridinethiol (2-PyT) quencher. Through an upward-curving Stern-Volmer plot, the system shows complex fluorescence quenching with a combination of static and dynamic quenching processes. To analyze the static quenching constant (V) by a "sphere of action" model, the collisional encounter between the Au(8) -cluster and 2-PyT presents a quenching radius (r) ≈5.8 nm, which is larger than the sum of the radii of the Au(8) -cluster and 2-PyT. This implies that fluorescence quenching can occur even though the Au(8) -cluster and 2-PyT are not very close to each other. The quenching pathway may be derived from a photoinduced electron-transfer process of the encounter pair between the Au(8) -cluster (as an electron donor) and 2-PyT (as an electron acceptor) to allow efficient fluorescence quenching in the absence of coupling reagents. Interestingly, the fluorescence is restored by oxidation of 2-PyT to form the corresponding disulfide compound and then quenched again after the reduction of the disulfide. This redox-switchable fluorescent Au(8) -cluster platform is a novel discovery, and its utility as a promising sensor for detecting H(2) O(2) -generating enzymatic transformations is demonstrated.