Toxic Reactive Oxygen Species Research Articles

“Three birds with one stone” nanoplatform: Efficient near‐infrared‐triggered type‑I AIE photosensitizer for mitochondria‐targeted photodynamic therapy against hypoxic tumors

AbstractCurrently three major problems seriously limit the practical application of cancer photodynamic therapy (PDT): (i) the hypoxic tumor microenvironment (TME); (ii) low generation efficiency of toxic reactive oxygen species (ROS) in aggregates and (iii) shallow tissue penetration depth of excitation light. Very limited approaches are available for addressing all the above three problems with a single design. Herein, a rational “three birds with one stone” molecular and nanoengineering strategy is demonstrated: a photodynamic nanoplatform U‐Ir@PAA‐ABS based on the covalent combination of lanthanide‐doped upconversion nanoparticles (UCNPs) and an AIE‐active dinuclear Ir(III) complex provides a low oxygen concentration‐dependent type‐I photochemical process upon 980 nm irradiation by Föster resonance energy transfer (FRET). U‐Ir@PAA‐ABS targets mitochondria and has excellent phototoxicity even in severe hypoxia environments upon 980 nm irradiation, inducing a dual‐mode cell death mechanism by apoptosis and ferroptosis. Taken together, the in vitro and in vivo results demonstrate a successful strategy for improving the efficacy of PDT against hypoxic tumors.

A pH-sensitive imidazole grafted polymeric micelles nanoplatform based on ROS amplification for ferroptosis-enhanced chemodynamic therapy

Highly toxic reactive oxygen species (ROS), crucial in inducing apoptosis and ferroptosis, are pivotal for cell death pathways in cancer therapy. However, the effectiveness of ROS-related tumor therapy is impeded by the limited intracellular ROS and substrates, coupled with the presence of abundant ROS scavengers like glutathione (GSH). In this research, we developed acid-responsive, iron-coordinated polymer nanoparticles (PPA/TF) encapsulating a mitochondrial-targeting drug alpha-tocopheryl succinate (α-TOS) for enhanced synergistic tumor treatment. The imidazole grafted micelles exhibit prolonged blood circulation and improve the delivery efficiency of the hydrophobic drug α-TOS. Additionally, PPA's design aids in delivering Fe3+, supplying ample iron ions for chemodynamic therapy (CDT) and ferroptosis through the attachment of imidazole groups to Fe3+. In the tumor's weakly acidic intracellular environment, PPA/TF facilitates pH-responsive drug release. α-TOS specifically targets mitochondria, generating ROS and replenishing those depleted by the Fenton reaction. Moreover, the presence of Fe3+ in PPA/TF amplifies ROS upregulation, promotes GSH depletion, and induces oxidative damage and ferroptosis, effectively inhibiting tumor growth. This research presents an innovative ROS-triggered amplification platform that optimizes CDT and ferroptosis for effective cancer treatment.

Copper ion incorporation in α-synuclein amyloids.

Copper ion dys-homeostasis is linked to neurodegenerative diseases involving amyloid formation. Even if many amyloidogenic proteins can bind copper ions as monomers, little is known about copper interactions with the resulting amyloid fibers. Here, we investigate copper interactions with α-synuclein, the amyloid-forming protein in Parkinson's disease. Copper (Cu(II)) binds tightly to monomeric α-synuclein in vitro involving the N-terminal amine and the side chain of His50. Using purified protein and biophysical methods in vitro, we reveal that copper ions are readily incorporated into the formed amyloid fibers when present at the start of aggregation reactions, and the metal ions also bind if added to pre-formed amyloids. Efficient incorporation is observed for α-synuclein variants with perturbation of either one of the high-affinity monomer copper-binding residues (i.e., N-terminus or His50) whereas a variant with both N-terminal acetylation and His50 substituted with Ala does not incorporate any copper into the amyloids. Both the morphology of the resulting α-synuclein amyloids (amyloid fiber pitch, secondary structure, proteinase sensitivity) and the copper chemical properties (redox activity, chemical potential) are altered when copper is incorporated into amyloids. We speculate that copper chelation by α-synuclein amyloids contributes to the observed copper dys-homeostasis (e.g., reduced bioavailable levels) in Parkinson's disease patients. At the same time, amyloid-copper interactions may be protective to neuronal cells as they will shield aberrantly free copper ions from promotion of toxic reactive oxygen species.

The REV-ERB antagonist SR8278 modulates keratinocyte viability in response to UVA and UVB radiation.

The nucleotide excision repair (NER) system removes UV photoproducts from genomic DNA and is controlled by the circadian clock. Given that small-molecule compounds have been developed to target various clock proteins, we examined whether the cryptochrome inhibitor KS15 and REV-ERB antagonist SR8278 could modulate keratinocyte responses to UV radiation invitro. We observed that though SR8278 promoted cell viability in UVB-irradiated cells, it had little effect on NER or on the expression of the clock-regulated NER factor XPA. Rather, we found that both KS15 and SR8278 absorb light within the UV spectrum to limit initial UV photoproduct formation in DNA. Moreover, SR8278 promoted UVB viability even in cells in which the core circadian clock protein BMAL1 was disrupted, which indicates that SR8278 is likely acting via other REV-ERB transcriptional targets. We further observed that SR8278 sensitized keratinocytes to light sources containing primarily UVA wavelengths of light likely due to the generation of toxic reactive oxygen species. Though other studies have demonstrated beneficial effects of SR8278 in other model systems, our results here suggest that SR8278 has limited utility for UV photoprotection in the skin and will likely cause phototoxicity in humans or mammals exposed to solar radiation.

Aluminum enhances the oxidative damage of ZnO NMs in the human neuroblastoma SH-SY5Y cell line

Bare and doped zinc oxide nanomaterials (ZnO NMs) are of great interest as multifunctional platforms for biomedical applications. In this study, we systematically investigate the physicochemical properties of Aluminum doped ZnO (AZO) and its bio-interactions with neuroblastoma (SH-SY5Y) and red blood (RBCs) cells. We provide a comprehensive chemical and structural characterization of the NMs. We also evaluated the biocompatibility of AZO NMs using traditional toxicity assays and advanced microscopy techniques. The toxicity of AZO NMs towards SH-SY5Y cells, decreases as a function of Al doping but is higher than the toxicity of ZnO NMs. Our results show that N-acetyl cysteine protects SH-SY5Y cells against reactive oxygen species toxicity induced by AZO NMs. ZnO and AZO NMs do not exert hemolysis in human RBCs at the doses that cause toxicity (IC50) in neuroblastoma cells. The Atomic force microscopy qualitative analysis of the interaction of SH-SY5Y cells with AZO NMs shows evidence that the affinity of the materials with the cells results in morphology changes and diminished interactions between neighboring cells. The holotomographic microscopy analysis demonstrates NMs' internalization in SH-SY5Y cells, changes in their chemical composition, and the role of lipid droplets in the clearance of toxicants.Graphical

Metabolic Nanoregulator Remodels Gut Microenvironment for Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is strongly related to the occurrence of accumulation of toxic reactive oxygen species (ROS), inflammation of the mucosa, and an imbalance of intestinal microbes. However, current treatments largely focus on a single factor, yielding unsatisfactory clinical outcomes. Herein, we report a biocompatible and IBD-targeted metabolic nanoregulator (TMNR) that synergistically regulates cellular and bacterial metabolism. The TMNR comprises a melanin-gallium complex (MNR) encapsulated within a thermosensitive and colitis-targeting hydrogel, all composed of natural and FDA-approved components. The TMNR confers superior broad-spectrum antioxidant properties, effectively scavenging reactive oxygen species (ROS) and blocking inflammatory signaling pathways. The presence of Ga3+ in TMNR selectively disrupts iron metabolism in pathogenic microorganisms due to its structural resemblance to the iron atom. Additionally, incorporating a thermosensitive injectable hydrogel enables targeted delivery of TMNR to inflammatory regions, prolonging their retention time and providing a physical barrier function for optimizing IBD treatment efficacy. Collectively, TMNR effectively modulates the redox balance of inflamed colonic epithelial tissue and disrupts iron metabolism in pathogenic microorganisms, thereby eliminating inflammation and restoring intestinal homeostasis against IBD. Hence, this work presents a comprehensive approach for precise spatiotemporal regulation of the intestinal microenvironmental metabolism for IBD treatment.

Endoperoxide-enhanced self-assembled ROS producer as intracellular prodrugs for tumor chemotherapy and chemodynamic therapy.

Prodrug-based self-assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH-responsive ARS-4-hydroxybenzoyl hydrazide (HBZ)-5-amino levulinic acid (ALA) nanoparticles (AHA NPs) with self-supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS-HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS-HBZ for excellent anti-tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.

In Situ Piezoelectric-Catalytic Anti-Inflammation Promotes the Rehabilitation of Acute Spinal Cord Injury in Synergy.

Relieving inflammation via scavenging toxic reactive oxygen species (ROS) during the acute phase of spinal cord injury (SCI) proves to be an effective strategy to mitigate secondary spinal cord injury and improve recovery of motor function. However, commonly used corticosteroid anti-inflammatory drugs show adverse side effects which may induce increased risk of wound infection. Fortunately, hydrogen (H2), featuring selective antioxidant performance, easy penetrability, and excellent biosafety, is being extensively investigated as a potential anti-inflammatory therapeutic gas for the treatment of SCI. In this work, by a facile in situ growth approach of gold nanoparticles (AuNPs) on the piezoelectric BaTiO3, a particulate nanocomposite with Schottky heterojunction (Au@BT) is synthesized, which can generate H2 continuously by catalyzing H+ reduction through piezoelectric catalysis. Further, theoretical calculations are employed to reveal the piezoelectric catalytic mechanism of Au@BT. Transcriptomics analysis and nontargeted large-scale metabolomic analysis reveal the deeper mechanism of the neuroprotective effect of H2 therapy. The as-prepared Au@BT nanoparticle is first explored as a flexible hydrogen gas generator for efficient SCI therapy. This study highlights a promising prospect of nanocatalytic medicine for disease treatments by catalyzing H2 generation; thus, offering a significant alternative to conventional approaches against refractory spinal cord injury.

Characterization of OsPIN2 Mutants Reveal Novel Roles for Reactive Oxygen Species in Modulating Not Only Root Gravitropism but Also Hypoxia Tolerance in Rice Seedlings.

Tolerance to submergence-induced hypoxia is an important agronomic trait especially for crops in lowland and flooding-affected areas. Although rice (Oryza sativa) is considered a flood-tolerant crop, only limited cultivars display strong tolerance to prolonged submergence and/or hypoxic stress. Therefore, characterization of hypoxic resistant genes and/or germplasms have important theoretical and practical significance for rice breeding and sustained improvements. Previous investigations have demonstrated that loss-of-function of OsPIN2, a gene encoding an auxin efflux transporter, results in the loss of root gravitropism due to disrupted auxin transport in the root tip. In this study, we revealed a novel connection between OsPIN2 and reactive oxygen species (ROS) in modulating root gravitropism and hypoxia tolerance in rice. It is shown that the OsPIN2 mutant had decreased accumulation of ROS in root tip, due to the downregulation of glycolate oxidase encoding gene OsGOX6, one of the main H2O2 sources. The morphological defects of root including waved rooting and agravitropism in OsPIN2 mutant may be rescued partly by exogenous application of H2O2. The OsPIN2 mutant exhibited increased resistance to ROS toxicity in roots due to treatment with H2O2. Furthermore, it is shown that the OsPIN2 mutant had increased tolerance to hypoxic stress accompanied by lower ROS accumulation in roots, because the hypoxia stress led to over production of ROS in the roots of the wild type but not in that of OsPIN2 mutant. Accordingly, the anoxic resistance-related gene SUB1B showed differential expression in the root of the WT and OsPIN2 mutant in response to hypoxic conditions. Notably, compared with the wild type, the OsPIN2 mutant displayed a different pattern of auxin distribution in the root under hypoxia stress. It was shown that hypoxia stress caused a significant increase in auxin distribution in the root tip of the WT but not in that of the war1 mutant. In summary, these results suggested that OsPIN2 may play a role in regulating ROS accumulation probably via mediating auxin transport and distribution in the root tip, affecting root gravitropism and hypoxic tolerance in rice seedlings. These findings may contribute to the genetic improvement and identification of potential hypoxic tolerant lines in rice.

Nanomaterials for Ultrasound Imaging- Guided Sonodynamic Therapy.

Ultrasound examination is becoming the most popular medical imaging modality because of its low cost and high safety profile. Ultrasound contrast agents enhance the scattering of sound waves, which can improve the clarity and resolution of images. Nanoparticle Ultrasound contrast agents have the characteristics of a large specific surface area and a modifiable surface, which can increase drug loading capacity, prolong circulation time, and enable drug enrichment in specific organs or tissues. This leads to improved therapeutic effects and reducing toxic and side effects. Compared with traditional ultrasound contrast agents, Nano-ultrasound contrast agents overcome the limitation of imaging solely within blood vessels and facilitate imaging within tumor tissues, thereby extending the duration of enhanced imaging. Sonodynamic therapy is an emerging treatment method that has been developed rapidly in recent years, which has the advantages of noninvasive, high spatial and temporal resolution, and low toxicity and side effects. Sonodynamic therapy utilizes a sonosensitizer that, when excited by ultrasound at the tumor site, produces toxic reactive oxygen species, inducing apoptosis or necrosis in tumor cells. Ultrasound-guided sonodynamic therapy allows for real-time observation of lesions, is convenient and flexible, and is free of radiation exposure. With the use of nanomaterials as carriers, ultrasound-guided sonodynamic therapy has made significant strides. This study categorizes and summarizes the current research on acoustic sensitizer carrier materials, including carbon-based, silicon-based, peptide-based, iron-based, metal-organic frameworks, polymers, and liposomes. It concludes by highlighting the current challenges in the integration of ultrasound imaging with sonodynamic therapy and suggests future directions for clinical application development.

Biofilm Microenvironment-Sensitive Piezoelectric Nanomotors for Enhanced Penetration and ROS/NO Synergistic Bacterial Elimination.

Sonodynamic therapy offers a highly accurate treatment for bacterial infections; however, its antibacterial efficacy is hindered by bacterial biofilms that limit the penetration of sonosensitizers. Herein, a nitric oxide (NO)-driven mushroom-like Janus nanomotor (BT@PDA-La) based on the unilateral coating of polydopamine (PDA) on piezoelectric tetragonal barium titanate (BT) and further modified with l-arginine (l-Arg) on the PDA side is fabricated. In the infected microenvironment with high levels of H2O2, NO is produced unilaterally from BT@PDA-La, thus leading to its self-propelled movement and facilitating its permeability in the biofilm. Under ultrasonic vibrations, the piezoelectric effect of BT@PDA-La is triggered by the exogenous mechanical wave, and toxic reactive oxygen species (ROS) are efficiently generated via an in situ catalytic reaction. The synergistic treatment with ROS/NO achieved the destruction of biofilms and embedded drug-resistant bacteria in vitro. Importantly, BT@PDA-La exhibits excellent biofilm penetration capacity, effectively eliminating biofilm infection while accelerating the healing of infected muscles by alleviating oxidative stress, regulating inflammatory factors, and accelerating angiogenesis. Collectively, this study provides a promising strategy for enhancing the penetration of pathological environment-driven nanomaterials through biofilms and advances the application of nanomotors for the therapy of bacterial infections in clinical medicine.

Activation of the PPARγ/NF-κB pathway by A-MPDA@Fe3O4@PVP via scavenging reactive oxygen species to alleviate hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (IRI) is a common pathological process during hepatectomy and liver transplantation and the two primary reasons for hepatic IRI are reactive oxygen species (ROS)-mediated oxidative stress and excessive inflammatory responses. Herein, a novel antioxidant nanodrug (A-MPDA@Fe3O4@PVP) is prepared by employing L-arginine-doped mesoporous polydopamine (A-MPDA) nanoparticles as the carrier for deposition of ultra-small ferric oxide (Fe3O4) nanoparticles and further surface modification with polyvinylpyrrolidone (PVP). A-MPDA@Fe3O4@PVP not only effectively reduces the aggregation of ultra-small Fe3O4, but also simultaneously replicates the catalytic activity of catalase (CAT) and superoxide dismutase (SOD). A-MPDA@Fe3O4@PVP with good antioxidant activity can rapidly remove various toxic reactive oxygen species (ROS) and effectively regulate macrophage polarization in vitro. In the treatment of hepatic IRI, A-MPDA@Fe3O4@PVP effectively alleviates ROS-induced oxidative stress, reduces the expression of inflammatory factors, and prevents apoptosis of hepatocytes through immune regulation. A-MPDA@Fe3O4@PVP can further protect liver tissue by activating the PPARγ/NF-κB pathway. This multiplex antioxidant enzyme therapy can provide new references for the treatment of IRI in organ transplantation and other ROS-related injuries such as fibrosis, cirrhosis, and bacterial and hepatic viral infection.

Hypoxia and Singlet Oxygen Dual-Responsive Micelles for Photodynamic and Chemotherapy Therapy Featured with Enhanced Cellular Uptake and Triggered Cargo Delivery.

Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and singlet oxygen-responsive polymeric micelles which contain azo and nitroimidazole groups for enhanced cellular uptake, repaid cargo release, and codelivery of photosensitizer Ce6 and hypoxia-activated prodrug tirapazamine TPZ (DHM-Ce6@TPZ), which could be used for combining Ce6-mediated photodynamic therapy (PDT) and PDT-activated chemotherapy to enhance the therapy effect of cancer. The hypoxia- and singlet oxygen-responsive polymeric micelles DHM-Ce6@TPZ were prepared by film hydration method. The morphology, physicochemical properties, stimuli responsiveness, in vitro singlet oxygen production, cellular uptake, and cell viability were evaluated. In addition, the in vivo therapeutic effects of the micelles were verified using a tumor xenograft mice model. The resulting dual-responsive micelles not only increased the concentration of intracellular photosensitizer and TPZ, but also facilitated photosensitizer and TPZ release for enhanced integration of photodynamic and chemotherapy therapy. As a photosensitizer, Ce6 induced PDT by generating toxic singlet reactive oxygen species (ROS), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy, thereby evoking a synergistic photodynamic and chemotherapy therapeutic effect. The cascade synergistic therapeutic effect of DHM-Ce6@TPZ was effectively evaluated both in vitro and in vivo to inhibit tumor growth in a breast cancer mice model. The designed multifunctional micellar nano platform could be a convenient and powerful vehicle for the efficient co-delivery of photosensitizers and chemical drugs for enhanced synergistic photodynamic and chemotherapy therapeutic effect of cancer.

Nano iron doped calcium phosphates act as pH-Sensitive and biodegradable peroxidase-like nanozymes for cancer chemodynamic therapy and MRI contrast

All types of cancer are a threat to human health and among the current therapies, the highly invasive chemotherapy is still the standard in several cases. Currently, more specific and less invasive therapies are being developed and chemodynamic therapy arose as a viable alternative. This strategy takes advantage of the tumour biochemical characteristics such as the acidic pH (∼6.0) and the high concentration of H2O2 (∼50 μM–∼1 mM). In these specific conditions, nanoparticles with peroxidase-like catalytic properties can convert H2O2 into highly toxic reactive oxygen species that induce oxidative stress in cancer cells. One of the remarkable advantages of chemodynamic therapy concerns the peroxidase-like activity, which only occurs in specific pH environments, as found in the tumour microenvironment. At the same time, the produced reactive oxygen species are short-lived, meaning that they will not travel outside the tumoral region, thus not affecting healthy surrounding tissues.This work reports on the production and characterization of iron doped calcium phosphate nanoparticles, as a fully biodegradable alternative to existing chemodynamic agents. By incorporating iron in different oxidation states into the lattice through calcium substitution, these nanoparticles exhibit high catalytic conversion of H2O2 into reactive oxygen species, more specifically into the hydroxyl radical, independently of the iron oxidation state. Outstanding results concern the significant toxicity, only obtained at pH 6.0 and in the presence of H2O2, while remaining non-toxic in physiological conditions (pH7.4) when tested against triple negative breast cancer cells, thus proving the specificity of the treatment in tumoral conditions. Moreover, the presented magnetic properties allowed them to produce significant contrast in magnetic resonance imaging, with different results depending on the iron oxidation state.

Casiopeina III-ia: A Copper Compound with Potential Use for Treatment of Infections Caused by Leishmania mexicana

Introduction: Casiopeina III-ia (CasIII-ia) is a mixed chelate copper (II) compound capable of interacting with free radicals generated in the respiratory chain through redox reactions, producing toxic reactive oxygen species (ROS) that compromise the viability of cancer cells, bacteria and protozoa. Due to its remarkable effect on protozoa, this study evaluated the effect of CasIII-ia on Leishmania mexicana amastigotes and its potential use as a treatment for cutaneous leishmaniasis in the murine model. Methods: We analyzed the leishmanicidal effect of CasIII-ia on L. mexicana amastigotes and on their survival in bone marrow-derived macrophages. Furthermore, we evaluated the production of ROS in treated parasites and the efficacy of CasIII-ia in the treatment of mice infected with L. mexicana. Results: Our results show that CasIII-ia reduces parasite viability in a dose-dependent manner that correlates with increased ROS production. A decrease in the size of footpad lesions and in parasite loads was observed in infected mice treated with the intraperitoneal administration of CasIII-ia. Conclusions: We propose CasIII-ia as a potential drug for the treatment of cutaneous leishmaniasis.

Low-dose X-ray stimulated NO-releasing nanocomposites for closed-loop dual-mode cancer therapy.

X-ray-excited photodynamic therapy (X-PDT) employs X-rays as an energy source, overcoming the light penetration limitations of traditional photodynamic therapy (PDT) but is constrained by high-energy radiation and the hypoxic tumor microenvironment. Low-dose X-ray-excited photodynamic therapy and reduction of mitochondrial oxygen consumption can serve as significant breakthroughs in overcoming these barriers. In this study, NaLuF4:Tb/Gd (15%/5%)@NaYF4 (ScNP) nanoparticles adsorbing the photosensitizer MC540 and loaded with α-(nitrate ester) acid (NEAA) were prepared as low X-ray dose triggered nano-scintillators. The final product obtained was NaLuF4:Tb/Gd (15%/5%)@NaYF4@mSiO2@MC540@NEAA (ScNP-MS@MC540@NEAA) nanocomposites, which exhibited intense green luminescence. X-PDT generates cytotoxic reactive oxygen species (ROS) with minimal ionizing radiation damage. Simultaneously, NEAA reacts with glutathione (GSH) to generate nitric oxide (NO) for gaseous treatment of the damaged mitochondrial respiratory chain to reduce oxygen consumption and alleviate hypoxia, enhancing the X-PDT efficacy and realizing a closed-loop treatment. The superoxide ions (˙O2-) can rapidly react with NO produced to form the highly cytotoxic reactive nitrogen species (RNS) peroxynitrite anion (ONOO-), which exhibits higher cytotoxicity compared to ROS. Furthermore, GSH scavenges toxic ROS and maintains the physiological function of tumor cells. It can induce cancer cell overoxidation and nitrosative stress. This work describes a low-dose X-ray-triggered X-PDT system with total radiation of 50 mGy, which involves GSH consumption, self-supplied NO, mitochondrial damage alleviation, and hypoxia relief to generate ROS and RNS, forming a closed-loop anti-hypoxia dual-mode system with synergistically enhanced anti-tumor effects, without significant biological side effects. It provides a promising platform for deep-seated tumor X-PDT with considerable application prospects.

Tau‑targeting multifunctional nanocomposite based on tannic acid-metal for near-infrared fluorescence/magnetic resonance bimodal imaging-guided combinational therapy in Alzheimer's disease.

Rationale: Alzheimer's disease (AD) is hallmarked by amyloid-β (Aβ) plaques and hyperphosphorylated tau (p-tau) neurofibrillary tangles. While Aβ-centric therapies have shown promise, the complex pathology of AD requires a multifaceted therapeutic approach. The weak association between Aβ levels and cognitive decline highlights the need for alternative theranostic strategies. Currently, oxidative stress and tau hyperphosphorylation are now recognized as critical pathological events in AD. Thus, therapies that concurrently attenuate oxidative stress damage and inhibit tau pathology hold great potential for AD treatment. Methods: Herein, a multifunctional neuron-targeted nanocomposite is devised to realize dual imaging-guided AD therapy, integrating the inhibition of tau pathology and reactive oxygen species (ROS)-neutralizing biofunctions. The construction of the nanocomposite incorporates polyphenolic antioxidants tannic acid (TA)-based nanoparticles carrying manganese ions (Mn2+) and fluorescent dye IR780 iodide (IR780), coupled with a neuron-specific TPL peptide. The resulting IR780-Mn@TA-TPL nanoparticles (NPs) are comprehensively evaluated in both in vitro and in vivo AD models to assess their imaging capabilities and therapeutic efficacy. Results: The nanocomposite facilitates Mn-enhanced magnetic resonance (MR) imaging and near-infrared (NIR) fluorescence imaging. It effectively neutralizes toxic ROS and reduces tau hyperphosphorylation and aggregation. In AD rat models, the nanocomposite restores neuronal density in the hippocampus and significantly improves spatial memory. Conclusions: Such a neuron‑targeting multifunctional nanocomposite represents a potential theranostic strategy for AD, signifying a shift towards bimodal imaging-guided treatment approaches.

Improved effectiveness of X-PDT against human triple-negative breast cancer cells through the use of liposomes co-loaded with protoporphyrin IX and perfluorooctyl bromide.

In this study, we utilized X-ray-induced photodynamic therapy (X-PDT) against triple-negative breast cancer (TNBC) cells. To achieve this, we developed a liposome delivery system that co-loaded protoporphyrin IX (PPIX) and perfluorooctyl bromide (PFOB) in a rational manner. Low-dose X-ray at 2 Gy was employed to activate PPIX for the generation of reactive oxygen species (ROS), and the co-loading of PFOB provided additional oxygen to enhance ROS production. The resulting highly toxic ROS effectively induced cell death in TNBC. In vitro X-PDT effects, including intracellular ROS generation, cell viability, and apoptosis/necrosis assays in TNBC cells, were thoroughly investigated. Our results indicate that the nanocarriers effectively induced X-PDT effects with very low-dose radiation, making it feasible to damage cancer cells. This suggests the potential for the effective utilization of X-PDT in treating hypoxic cancers, including TNBC, with only a fraction of conventional radiotherapy.

Atomic-thick porous Pd nanosheets with antioxidant enzyme-like activities and photothermal properties for potential Alzheimer’s disease treatment

Nanostructure-based regulation on β-amyloid (Aβ) aggregation has shown potential in Alzheimer’s disease (AD) treatment. However, to develop an efficient therapeutic modality for Aβ-targeted AD therapy over nanostructures, with a deep understanding of mechanism at a molecular level, still remains a challenge. Herein, we report a multimodal modulation on Aβ aggregation by the subnanometer-thick and porous Pd nanosheets (NSs). The Pd NSs can not only effectively inhibit Aβ42 aggregation via a strong Pd-Aβ42 interaction, but display excellent antioxidant enzyme-like activities to eliminate the toxic reactive oxygen species (ROS) caused by the Aβ42 fibers, which restrains the ROS induced vicious cycle and slows down the development of AD. Besides, the Pd NSs exhibit robust near-infrared (NIR) photothermal effect, which enhances the depolymerization of Aβ42 fibers, while they are less cytotoxic and even promote cell growth. Moreover, the Pd NSs-based multimodal therapy can prolong the lifetime of nematodes and enhance their locomotion ability in in vivo tests. This work provides new insights into the development of ultrathin metallic nanostructures for AD therapy.

Photoresponsive metal-organic framework with combined photodynamic therapy and hypoxia-activated chemotherapy for the targeted treatment of rheumatoid arthritis

Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease process. In this study, we developed a novel photoresponsive targeted drug delivery system (TPNPs-HA) that can effectively deliver the hypoxia-activated prodrug tirapazamine (TPZ) specifically to activated macrophages. After administration, this metal-organic framework, PCN-224, constructed uing the photosensitizer porphyrin, exhibits the ability to generate excessive toxic reactive oxygen species (ROS) when exposed to near-infrared light. Additionally, the oxygen-consumed hypoxic environment further activates the chemotherapeutic effect of TPZ, thus creating a synergistic combination of photodynamic therapy (PDT) and hypoxia-activated chemotherapy (HaCT) to promote the elimination of activated M1-type macrophages. The results highlight the significantly potential of this photoresponsive nano-delivery system in providing substantial relief for RA. Furthermore, these findings support its effectiveness in inhibiting the disease process of RA, thereby offering new possibilities for the development of precise and accurate strategies for RA.