Photothermally Triggered Copper Payload Release for Cuproptosis-Promoted Cancer Synergistic Therapy

Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper-induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN-Cu/PEG/DSF) to realize on-demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu²⁺ in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu⁺ species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano-therapeutic platforms.     

Photocatalytic Generation of Hydrogen Radical (H⋅) with GSH for Photodynamic Therapy

As a reactive hydrogen species, the hydrogen radical (H⋅) scarcely sees applications in tumor biological therapy due to the very limited bio-friendly sources of H⋅. In this work, we report that TAF can act as an organic photosensitizer as well as an efficient photocatalytic H⋅ generator with reduced glutathione (GSH) as a fuel. The photoactivation of TAF leads to cell death in two ways including triple amplification of oxidative stress via ferroptosis-apoptosis under normoxia and apoptosis through biological reductions under hypoxia. TAF presents excellent biosafety with ultrahigh photocytotoxicity index at an order of magnitude of 10²–10³ on both normoxic and hypoxic cells. The in vitro data suggest that H⋅ therapy is promising to overcome the challenge of tumor hypoxia at low doses of both photocatalyst and light. In addition, the capability of near-infrared two-photon excitation would benefit broad biological applications.     

Engineered Metallacycle-Based Supramolecular Photosensitizers for Effective Photodynamic Therapy

Although metallacycle-based supramolecular photosensitizers (PSs) have attracted increasing attention in biomedicine, their clinical translation is still hindered by their inherent dark toxicity. Herein, we report what to our knowledge is the first example of a molecular engineering approach to building blocks of metallacycles for constructing a series of supramolecular PSs ( RuA–RuD ), with the aim of simultaneously reducing dark toxicity and enhancing phototoxicity, and consequently obtaining high phototoxicity indexes (PI). Detailed in vitro investigations demonstrate that RuA–RuD display high cancer cellular uptake and remarkable antitumor activity even under hypoxic conditions. Notably, RuD exhibited no dark toxicity and displayed the highest PI value (≈406). Theoretical calculations verified that RuD has the largest steric hindrance and the lowest singlet-triplet energy gap (ΔE_ST, 0.61 eV). Further in vivo studies confirmed that RuD allows safe and effective phototherapy against A549 tumors.     

Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy

Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.     

Metal-DNA Nanocomplexes Enhance Chemo-dynamic Therapy by Inhibiting Autophagy-Mediated Resistance

Chemo-dynamic therapy (CDT) based on the Fenton or Fenton-like reaction has emerged as a promising approach for cancer treatment. However, autophagy-mediated self-protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal-DNA nanocomplexes (DACs-Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn-based catalyst in DACs-Mn was used to generate highly hydroxyl radicals (⋅OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs-Mn inhibited the expression of autophagy-associated proteins, thereby improving the efficacy of CDT. By disrupting the self-protective pathway of cells under severe oxidative stress, this novel approach of DACs-Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor-specific oxidative damage. Notably, the Metal-DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.     

Metal-based nanoparticles for cardiovascular disease diagnosis and therapy

Cardiovascular diseases (CVDs) are the most prominent cause of disability and mortality in the world. Although there have been a variety of therapeutic options for the management of CVDs, most of the traditional therapeutic strategies could not sufficiently stop or reduce the progression of these diseases and may result in some side effects. With the advance in nanotechnology, a number of metal-based nanoparticles have been developed and shown promising potentials in the treatment of CVDs. In this review, we provide a comprehensive review of researches on recent development of metal-based nanoparticles in diagnosis and therapy in CVDs as biomedical materials. We also discuss the challenges in the clinical translation and potential risks in their application of CVD therapy. Based on the ongoing research and applications, we can conclude metal-based nanoparticles are expected to become potential therapeutics for the treatment of CVDs. But their application is still in its infancy and much more efforts should be made to enforce a clinical breakthrough.     

Tetracyanobutadiene Bridged Push-Pull Chromophores: Development of New Generation Optoelectronic Materials

This review describes the design strategies used for the synthesis of various tetracyanobutadiene bridged donor-acceptor molecular architectures by a click type [2+2] cycloaddition-retroelectrocyclization (CA-RE) reaction sequence. The photophysical and electrochemical properties of the tetracyanobutadiene bridged molecular architectures based on various moieties including diketopyrrolopyrrole, isoindigo, benzothiadiazole, pyrene, pyrazabole, truxene, boron dipyrromethene (BODIPY), phenothiazine, triphenylamine, thiazole and bisthiazole are summarized. Further, we discuss some important applications of the tetracyanobutadiene bridged derivatives in dye sensitized solar cells, bulk heterojunction solar cells and photothermal cancer therapy.