A Smart "Energy NanoLock" Selectively Blocks Oral Cancer Energy Metabolism through Synergistic Inhibition of Exogenous Nutrient Supply and Endogenous Energy Production.

The major challenge in oral cancer is the lack of state-of-the-art treatment modality that effectively cures cancer while preserving oral functions. Recent insights into tumor metabolic dependency provide a therapeutic opportunity for exploring optimal treatment approaches. Herein, a smart responsive "Energy NanoLock" is developed to improve cancer metabolic intervention by simultaneously inhibiting nutrient supply and energy production. NanoLock is a pomegranate-like nanocomplex of cyclicRGD-modified carboxymethyl chitosan (CyclicRC, pI = 6.7) encapsulating indocyanine green and apoptotic peptides functionalized gold nanoparticles (IK-AuNPs), which together form a dual pH- and photoresponsive therapeutic platform. NanoLock exhibits good stability under physiological conditions, but releases small-size CyclicRC and IK-AuNPs in response to the tumor acidic microenvironment, leading to deep tumor penetration. CyclicRC targets integrins to inhibit tumor angiogenesis, and consequently blocks tumor nutrient supply. Meanwhile, IK-AuNPs specifically induce apoptotic peptides and photothermally mediated mitochondrial collapse, and consequently inhibits endogenous energy production, thereby facilitating cell death. Importantly, in both xenograft and orthotopic oral cancer models, NanoLock selectively eliminates tumors with little cross-reactivity with normal tissues, especially oral functions, resulting in prolonged survival of mice. Therefore, NanoLock provides a novel metabolic therapy to exploit synergistic inhibition of exogenous nutrient supply and endogenous energy production, which potentially advances oral cancer treatment.

Highly Conductive and Compliant Silver Nanowire Nanocomposites by Direct Spray Deposition.

The silver nanowire (Ag NW)/elastomer nanocomposite represents a prototypical form of a compliant conductor for flexible and stretchable electronic devices. The widespread implementations are currently hindered by the complicated procedures to effectively disperse Ag NWs into elastomer matrices. In this study, we report a facile and scalable coating process to create Ag NW nanocomposites on various flexible/stretchable substrates. As-synthesized Ag NWs from the high-yield polyol-reduction approach are homogeneously dispersed into a variety of dilute elastomer solutions, thereby enabling direct spray deposition into highly compliant conductors. The as-prepared nanocomposite exhibits excellent conductivity (∼11,000 S/cm) and high deformability to 100% strain. The stable electrical properties are largely retained under repetitive mechanical manipulations including stretching, bending, and folding. The patterned features of conductive nanocomposites are conveniently accessed using shadow masks or selective laser ablation. The practical suitability is demonstrated by the successful implementations of a stretchable sensing patch and a flexible light-emitting diode display.

Integrative Strategy for Investigating the Interactions between STING and Small-Molecule Ligands.

Although small-molecule agonists of stimulator of interferon genes (STING) show significance in activating the immune system, the dynamic process involved in ligands activating STING remains unclear. Herein, we developed a biochemical strategy, integrating computer simulation and a biochemical engineering approach, to reveal the interaction mechanism between STING and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an agonist that activates the TANK binding kinase 1-interferon regulatory factor 3 signaling pathway. Specifically, inspired by an analysis of the STING-DMXAA crystal structure, we designed and synthesized DMXAA derivatives to investigate the STING-DMXAA binding model. We identified that the carboxyl moiety of DMXAA was a major pharmacophore responsive to STING activation. In particular, the loss of hydrogen bond interaction between the carboxylic acid of DMXAA and the side chain Thr262 of STING led to STING inhibition. DMXAA N-methyl amide derivative (DNHM) exhibited good inhibitor activity, inhibited STING-mediated interferon production in vitro and in vivo, and effectively attenuated STING-associated inflammatory diseases. Therefore, we provide a new insight into STING-ligand interactions, which may improve the understanding of STING biology.