Ultrathin BSA-Stabilized Black Phosphorous Nanoreactor Boosts Mild-Temperature Photothermal Therapy Through Modulation of Cellular Self-Defense Fate.

Mild-temperature photothermal therapy (mild-PTT, 42-45 °C) offers a higher level of biosafety. However, its therapeutic effects are compromised by the heat shock response (HSR), a cellular self-defense mechanism, which triggers the overexpression of heat shock proteins (HSPs) with the capacity of repairing the damaged tumor cells. Herein, this work fabricates a novel nanoreactor by incorporating up-conversion nanoparticles (UCNPs), chlorin e6 (Ce6), and glucose oxidase (GOx) onto the ultrathin black phosphorus nanosheet (BPNS) (denoted as GOx-BUC). This nanoreactor amplifies mild-PTT effects under irradiation with an 808 nm laser, modulating HSPs-mediated cellular self-defense fate. On one hand, upon irradiation with a 980 nm laser, UCNPs can transfer energy to excite Ce6, leading to the generation of ROS burst, which achieves indiscriminate damage to HSPs activity in deeper tumor tissues. On the other hand, GOx can consume glucose, thereby depleting the ATP energy supply and further suppressing HSPs expression. Consequently, GOx-BUC exhibits excellent anti-tumor efficacy under mild temperature in a human colorectal cancer mouse model, resulting in complete tumor inhibition with negligible side effects. This black phosphorous nanoreactor, featuring dual-track HSPs destruction functionality, introduces novel perspectives for enhancing mild-PTT effectiveness while maintaining high biosafety.

Regenerating Chemotherapeutics through Copper-Based Nanomedicine: Disrupting Protein Homeostasis for Enhanced Tumor Therapy.

The bis-(diethyldithiocarbamate)-copper (CuET), the disulfiram (DSF)-Cu complex, has exhibited noteworthy anti-tumor property. However, its efficacy is compromised due to the inadequate oxidative conditions and the limitation of bioavailable copper. Because CuET can inactivate valosin-containing protein (VCP), a bioinformatic pan-cancer analysis of VCP is first conducted in this study to identify CuET as a promising anticancer drug for diverse cancer types. Then, based on the drug action mechanism, a nanocomposite of CuET and copper oxide (CuO) is designed and fabricated utilizing bovine serum albumin (BSA) as the template (denoted as CuET-CuO@BSA, CCB). CCB manifests peroxidase (POD)-mimicking activity to oxidize the tumor endogenous H2O2 to generate reactive oxygen species (ROS), enhancing the chemotherapy effect of CuET. Furthermore, the cupric ions released after enzymatic reaction can regenerate CuET, which markedly perturbs intracellular protein homeostasis and induces apoptosis of tumor cells. Meanwhile, CCB triggers cuproptosis by inducing the aggregation of lipoylated proteins. The multifaceted action of CCB effectively inhibits tumor progression. Therefore, this study presents an innovative CuET therapeutic strategy that creates an oxidative microenvironment in situ and simultaneously self-supply copper source for CuET regeneration through the combination of CuO nanozyme with CuET, which holds promise for application of CuET for effective tumor therapy.

Black Phosphorus/MnO2 Nanocomposite Disrupting Bacterial Thermotolerance for Efficient Mild-Temperature Photothermal Therapy.

The emergence of multi-drug resistant (MDR) pathogens is a major public health concern, posing a substantial global economic burden. Photothermal therapy (PTT) at mild temperature presents a promising alternative to traditional antibiotics due to its biological safety and ability to circumvent drug resistance. However, the efficacy of mild PTT is limited by bacterial thermotolerance. Herein, a nanocomposite, BP@Mn-NC, comprising black phosphorus nanosheets and a manganese-based nanozyme (Mn-NZ) is developed, which possesses both photothermal and catalytic properties. Mn-NZ imparts glucose oxidase- and peroxidase-like properties to BP@Mn-NC, generating reactive oxygen species (ROS) that induce lipid peroxidation and malondialdehyde accumulation across the bacterial cell membrane. This process disrupts unprotected respiratory chain complexes exposed on the bacterial cell membrane, leading to a reduction in the intracellular adenosine triphosphate (ATP) content. Consequently, mild PTT mediated by BP@Mn-NC effectively eliminates MDR infections by specifically impairing bacterial thermotolerance because of the dependence of bacterial heat shock proteins (HSPs) on ATP molecules for their proper functioning. This study paves the way for the development of a novel photothermal strategy to eradicate MDR pathogens, which targets bacterial HSPs through ROS-mediated inhibition of bacterial respiratory chain activity.

pH-sensitive gold nanoclusters labeling with radiometallic nuclides for diagnosis and treatment of tumor.

The acidic microenvironment is one of the remarkable features of tumor and is also a reliable target for tumor theranostics. Ultrasmall gold nanoclusters (AuNCs) have good in vivo behaviors, such as non-retention in liver and spleen, renal clearance, and high tumor permeability, and held great potential for developing novel radiopharmaceuticals. Herein, we developed pH-sensitive ultrasmall gold nanoclusters by introducing quaternary ammonium group (TMA) or tertiary amine motifs (C6A) onto glutathione-coated AuNCs (TMA/GSH@AuNCs, C6A-GSH@AuNCs). Density functional theory simulation revealed that radiometal 89Sr, 223Ra, 44Sc, 90Y, 177Lu, 89Zr, 99mTc, 188Re, 106Rh, 64Cu, 68Ga, and 113Sn could stably dope into AuNCs. Both TMA/GSH@AuNCs and C6A-GSH@AuNCs could assemble into large clusters responding to mild acid condition, with C6A-GSH@AuNCs being more effective. To assess their performance for tumor detection and therapy, TMA/GSH@AuNCs and C6A-GSH@AuNCs were labeled with 68Ga, 64Cu, 89Zr and 89Sr, respectively. PET imaging of 4T1 tumor-bearing mice revealed TMA/GSH@AuNCs and C6A-GSH@AuNCs were mainly cleared through kidney, and C6A-GSH@AuNCs accumulated in tumors more efficiently. As a result, 89Sr-labeled C6A-GSH@AuNCs eradicated both the primary tumors and their lung metastases. Therefore, our study suggested that GSH-coated AuNCs held great promise for developing novel radiopharmaceuticals that specifically target the tumor acidic microenvironment for tumor diagnosis and treatments.

Tumor microenvironment-responsive nanohybrid for hypoxia amelioration with photodynamic and near-infrared II photothermal combination therapy.

Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has been widely investigated for tumor treatment. However, the limited tissue penetration depth of light in the near-infrared I (NIR-I) region and the hypoxic tumor microenvironment (TME) severely constrain their clinical applications. To address these challenges, in the present study, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumor. HA-Ce6-MnO2@SWNHs responded to the mild acidic TME to ameliorate tumor hypoxia, thus enhancing tumor PDT. Moreover, HA-Ce6-MnO2@SWNHs had a high photothermal conversion efficiency at 1064 nm (55.48%), which enabled deep tissue penetration (3.05 cm) and allowed for highly efficient tumor PTT in near-infrared II (NIR-II) window. PDT and PTT combination therapy with HA-Ce6-MnO2@SWNHs achieved a good therapeutic efficacy on 4T1 tumor-bearing mice, eradicating the primary tumors and suppressing cancer recurrence. Our study provides a promising strategy for developing a hypoxia relief and deep tissue penetration phototherapy platform by using SWNHs for highly effective tumor PDT and NIR-II PTT combination therapy. STATEMENT OF SIGNIFICANCE: The hypoxic tumor microenvironment (TME) and the limited penetration of the NIR-I light in biological tissues compromise the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT) on tumors. Here, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumors. The nanohybrid could efficiently accumulate in tumors through CD44-mediated active targeting. The sequential MnO2-enhanced PDT and efficient NIR-II PTT had a remarkable therapeutic effect by eliminating the primary tumor and simultaneously inhibiting tumor recurrence.

One-pot synthesis of 68Ga-doped ultrasmall gold nanoclusters for PET/CT imaging of tumors.

Gold nanoclusters (AuNCs) have attracted much attention for tumor theranostics in recent years because of their ability of renal clearance and to escape the reticuloendothelial system (RES) sequestration. In this study, we presented a novel method to synthesize 68Ga-doped (labeled) AuNCs by simultaneous reduction of 68GaCl3 and HAuCl4 by glutathione. As synthesized 68Ga-doped, glutathione-coated AuNCs (68Ga-GSH@AuNCs) were ultrasmall in size (<2 nm), highly stable under physiological conditions and renally clearable, and had high efficiency for tumor targeting. To demonstrate the universality of this 68Ga labeling method and further enhance tumor targeting efficiency, arginine-glycine-aspartate (RGD)-containing peptide was introduced as co-reductant to synthesize RGD peptide and glutathione co-coated, 68Ga-labeled AuNCs (68Ga-RGD-GSH@AuNCs). Introduction of RGD peptide did not interfere the synthesis process but significantly enhanced the tumor targeting efficiency of the AuNCs. Our study demonstrated that it was feasible to label AuNCs with gallium-68 by direct reduction of the radioisotope and HAuCl4 with reductant peptides, holding a great potential for clinical translation for PET/CT detection of tumors.

Gadolinium-porphyrin based polymer nanotheranostics for fluorescence/magnetic resonance imaging guided photodynamic therapy.

Nanotheranostics for fluorescence/magnetic resonance (FL/MR) dual-modal imaging guided photodynamic therapy (PDT) are highly desirable in precision and personalized medicine. In this study, a facile non-covalent electrostatic interaction induced self-assembly strategy is developed to effectively encapsulate gadolinium porphyrin (Gd-TCPP) into homogeneous supramolecular nanoparticles (referred to as Gd-PNPs). Gd-PNPs exhibit the following advantages: (1) excellent FL imaging property, high longitudinal relaxivity (16.157 mM-1 s-1), and good singlet oxygen (1O2) production property; (2) excellent long-term colloidal stability, dispersity and biocompatibility; and (3) enhanced in vivo FL/MR imaging guided tumor growth inhibition efficiency for CT 26 tumor-bearing mice. This study provides a new strategy to design and synthesize metalloporphyrin-based nanotheranostics for imaging-guided cancer therapy with enhanced theranostic properties.

Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy.

BACKGROUND: Recently, nanocatalyst-induced endoplasmic reticulum (ER) stress for cancer therapy has been attracting considerable attention. However, cancer cells are often able to overcome ER stress-induced death by activating the unfolded protein response (UPR), making nanocatalytic monotherapy a poor defense against cancer progression. PURPOSE: In this study, to improve the nanocatalytic treatment efficacy, a phase change material (PCM) was used to encapsulate the upstream ER stress initiator, iron oxide nanoparticles (Fe3O4 NPs), and the downstream UPR modulator, PR-619. Subsequently, the tumor-homing peptide tLyP-1 was coupled to it to form tLyP-1/PR-619/Fe3O4@PCM (tPF@PCM) theranostic platform. MATERIALS AND METHODS: tPF@PCM was synthesized using nanoprecipitation and resolidification methods followed by the EDC/NHS cross-linking method. The targeting capacity of tPF@PCM was evaluated in vitro and in vivo using flow cytometry and magnetic resonance imaging, respectively. The therapeutic efficacy of tPF@PCM was investigated in a renal cell carcinoma mouse model. Moreover, we explored the synergistic anti-tumor mechanism by examining the intracellular reactive oxygen species (ROS), aggregated proteins, ER stress response levels, and type of cell death. RESULTS: tPF@PCM had excellent tumor-targeting properties and exhibited satisfactory photothermal-enhanced tumor inhibition efficacy both in vitro and in vivo. Specifically, the phase transition temperature (45 °C) maintained using 808 nm laser irradiation significantly increased the release and catalytic activity of the peroxidase mimic Fe3O4 NPs. This strongly catalyzed the generation of hydroxyl radicals (•OH) via the Fenton reaction in the acidic tumor microenvironment. The redox imbalance subsequently resulted in an increase in the level of damaged proteins in the ER and initiated ER stress. Moreover, the pan-deubiquitinase inhibitor PR-619 blocked the "adaptive" UPR-mediated degradation of these damaged proteins, exacerbating the ER burden. Consequently, irremediable ER stress activated the "terminal" UPR, leading to apoptosis in cancer cells. CONCLUSION: This ER stress-exacerbating strategy effectively suppresses tumorigenesis, offering novel directions for advances in the treatment of conventional therapy-resistant cancers.

Metabolic Control by Heat Stress Determining Cell Fate to Ferroptosis for Effective Cancer Therapy.

Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe3O4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe3O4-containing nanoformulation (GBP@Fe3O4). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe3O4in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress.

Sequential PDT and PTT Using Dual-Modal Single-Walled Carbon Nanohorns Synergistically Promote Systemic Immune Responses against Tumor Metastasis and Relapse.

Immune responses stimulated by photodynamic therapy (PDT) and photothermal therapy (PTT) are a promising strategy for the treatment of advanced cancer. However, the antitumor efficacy by PDT or PTT alone is less potent and unsustainable against cancer metastasis and relapse. In this study, Gd3+ and chlorin e6 loaded single-walled carbon nanohorns (Gd-Ce6@SWNHs) are developed, and it is demonstrated that they are a strong immune adjuvant, and have high tumor targeting and penetration efficiency. Then, three in vivo mouse cancer models are established, and it is found that sequential PDT and PTT using Gd-Ce6@SWNHs synergistically promotes systemic antitumor immune responses, where PTT stimulates dendritic cells (DCs) to secrete IL-6 and TNF-α, while PDT triggers upregulation of IFN-γ and CD80. Moreover, migration of Gd-Ce6@SWNHs from the targeted tumors to tumor-draining lymph nodes sustainably activates the DCs to generate a durable immune response, which eventually eliminates the distant metastases without using additional therapeutics. Gd-Ce6@SWNHs intervened phototherapies also generate durable and long-term memory immune responses to tolerate and prevent cancer rechallenge. Therefore, this study demonstrates that sequential PDT and PTT using Gd-Ce6@SWNHs under moderate conditions elicits cooperative and long-lasting antitumor immune responses, which are promising for the treatment of patients with advanced metastatic cancers.

Design of Multiple Logic Gates Based on Chemically Triggered Fluorescence Switching of Functionalized Polyethylenimine.

In this study, two new functionalized polyethylenimine (PEI), PEIR and PEIQ, have been synthesized by covalently conjugating rhodamine 6G (R6G) or 8-chloroacetyl-aminoquinoline (CAAQ) and have been investigated for their sensing capabilities toward metal ions and anions basing on fluorescence on-off and off-on mechanisms. When triggered by protons, metal ions, or anions, functionalized PEIs can behave as a fluorescence switch, leading to a multiaddressable system. Inspired by these results, functionalized PEI-based logic systems capable of performing elementary logic operations (YES, NOT, NOR, and INHIBIT) and integrative logic operations (OR + INHIBIT) have been constructed by observing the change in the fluorescence with varying the chemical inputs such as protons, metal ions, and anions. Due to its characteristics, such as high sensitivity and fast response, developing functionalized PEI as a new material to perform logic operations may pave a new avenue to construct the next generation of molecular devices with better applicability for biomedical research.