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Lipoic Acid Capped Ag 2 S Quantum Dots for Mitochondria-Targeted NIR-II Fluorescence/Photoacoustic Imaging and Chemotherapy/Photothermal Treatment of Tumors
Hybrid nanosystems, such as those combining plasmonic, dielectric, and quantum-confined nanostructures, have long been of interest for enhancing and tailoring diverse light–matter interactions. Here, we present a series of hybrid nanomaterials exhibiting strongly enhanced nonlinear optical (NLO) properties, fabricated by combining silver sulfide quantum dots (Ag2S QDs) with silica and gold nanostructures. We studied their NLO properties (two-photon absorption and saturable absorption) in colloidal solutions over a wide spectral range (500–1600 nm) using the femtosecond Z-scan technique. Embedding Ag2S QDs into silica nanospheres gives rise to remarkable enhancement of two-photon absorption (up to a factor of 16 increase in the merit factor σ2/M compared to bare QDs), whereas covering such QD-doped silica nanospheres with gold nanoparticles or attaching the QDs to the surface of gold nanoshells (NSs) leads to even further enhancement (up to 73-fold increase in σ2/M), accompanied by a competing effect of saturable absorption. Furthermore, in the case of QD-doped silica spheres covered with a continuous gold layer, we observe a previously unreported saturation of extinction in the near-infrared region that follows an unusual intensity dependence, suggesting the involvement of two-photon absorption as the pumping mechanism. In addition to the experimental studies, we have performed numerical simulations, revealing the plasmonic origin of the observed spectral dependences of the NLO properties, with the underlying enhancement mechanisms involving local field enhancement and, possibly, also coupling between plasmon modes and QD excitons, giving rise to a double peak in the σ2 spectrum. Our findings demonstrate the unique potential of hybrid NLO nanomaterials combining quantum-confined, plasmonic, and dielectric components.
Herein, small‐sized fluorescent carbon nanoparticles (CNs) with tunable shapes ranging from spheres to various rods with aspect ratios (ARs) of 1.00, 1.51, 1.89, and 2.85 are prepared using a simple anion‐directed strategy for the first time. Based on comprehensive morphological and structural characteristics of CNs, along with theoretical calculations of density functional theory and molecular dynamics simulations, their shape‐control mechanism is attributed to interionic interactions‐induced self‐assembly, followed by carbonization. The endoplasmic reticulum‐targeting accuracy of CNs is gradually enhanced as their shape changes from spherical to higher‐AR rods, accompanied by a Pearson's correlation coefficient up to 0.90. This work presents a facile approach to control the shape of CNs and reveals the relationship between the shape and organelle‐targeting abilities of CNs, thereby providing a novel idea to synthesize CNs that serve as precise organelle‐targeted fluorescent probes.
Optical and photoacoustic imaging plays an important role in biomedical applications owing to its noninvasiveness and high resolution. Fluorescence imaging and photoacoustic imaging emerge as powerful tools to deconstruct molecular information and investigate biological processes in vivo. Despite great progress has been achieved in chemical probe synthesis, how to design probes with optimal fluorescence or photoacoustic imaging performance to dynamically visualize the biological process in vivo still faces challenges. From this perspective, we will focus on the advanced development of fluorescence and photoacoustic imaging in vivo. Furthermore, concerns and prospects for future imaging in vivo will be demonstrated.
The growth and metastasis of malignant solid tumors depend closely on new blood vessels. Vasculogenic mimicry provides a special pathway of blood supply during the early growth of malignant tumors, and real-time monitoring of its occurrence and development in vivo is important to clinical applications. However, there are few labels with sufficient brightness and stability in vivo to achieve high spatiotemporal resolution imaging of deep tissue for noninvasive optical detection of vasculogenic mimicry in tumor tissues. In this study, we constructed a high-brightness fluorescent label with fluorescence in the near-infrared-II region, which can be used not only for in vivo tumor imaging but also for tissue section imaging. Real-time high-resolution imaging of tumor vessels has been achieved with PbS quantum dots (QDs) surface-coupled with horseradish peroxidase (HRP) (HRP-QDs) by taking advantage of the low background autofluorescence of tissue at the near-infrared-II wavelength for in vivo and tissue section imaging. Qualitative and quantitative analysis of early blood supply patterns of tumor growth enables monitoring neovascularization to accurate noninvasive identification of benign and malignant solid tumors.
Photothermal therapy (PTT) is hampered by the limited capacity of light penetration, non-specific thermal diffusion damage to surrounding healthy tissues, and thermoresistance originating in heat shock proteins (HSPs). Here, a triple-respondent (triphosphate, glutathione, and pH) cascade nanoreactor was designed through the glucose consumption-induced thermal sensitization strategy. The near-infrared-II (NIR-II) photothermal reagent Bi–Au was encapsulated in a glucose oxidase-based protein–polyphenol structure with the help of the zeolitic imidazolate framework-8 (ZIF-8). The composite nanosystem possesses triple-enzyme activity (glucose oxidase, peroxidase-like, and catalase-like). On one hand, the product of hydrogen peroxide from glycolysis can be converted into reactive oxygen species and oxygen to enhance the chemodynamic therapy and alleviate the state of hypoxia in tumor cells. On the other hand, glucose consumption could down-regulate the expression level of HSPs. The heat resistance ability of cells decreased under starvation and oxidative damage states, which is beneficial to reduce the temperature required for PTT and improve the efficiency of mild PTT. The cascade nanocapsule exhibited high tumor inhibition and proposed a typical synergistic strategy for starvation, chemodynamic, and NIR-II mild photothermal therapy.
Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of therapeutic agents to mitochondria and efficient clearance of mtROS remain challenging. In the current study, we discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. Mechanistic studies revealed that this affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase and TA were assembled into complexes (hereafter referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging showed that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrated that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting NLRP3-mediated pyroptosis. More interestingly, TSC maintained superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases. This article is protected by copyright. All rights reserved.
We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH‐sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria‐mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A‐activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5‐fluorouracil (5‐FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft‐bearing mice that have a low response rate to 5‐FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor‐specific microenvironment‐activatable systems.
Lipoic acid (LA) is an organic compound that plays a key role in cellular metabolism. It participates in a posttranslational modification (PTM) named lipoylation, an event that is highly conserved and that occurs in multimeric metabolic enzymes of very distinct microorganisms such as Plasmodium sp. and Staphylococcus aureus, including pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KDH). In this mini review, we revisit the recent literature regarding LA metabolism in Plasmodium sp. and Staphylococcus aureus, by covering the lipoate ligase proteins in both microorganisms, the role of lipoate ligase proteins and insights for possible inhibitors of lipoate ligases.
Cancer has been one of the most common life-threatening diseases for a long time. Traditional cancer therapies such as surgery, chemotherapy (CT), and radiotherapy (RT) have limited effects due to drug resistance, unsatisfactory treatment efficiency, and side effects. In recent years, photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) have been utilized for cancer treatment owing to their high selectivity, minor resistance, and minimal toxicity. Accumulating evidence has demonstrated that selective delivery of drugs to specific subcellular organelles can significantly enhance the efficiency of cancer therapy. Mitochondria-targeting therapeutic strategies are promising for cancer therapy, which is attributed to the essential role of mitochondria in the regulation of cancer cell apoptosis, metabolism, and more vulnerable to hyperthermia and oxidative damage. Herein, the rational design, functionalization, and applications of diverse mitochondria-targeting units, involving organic phosphine/sulfur salts, quaternary ammonium (QA) salts, peptides, transition-metal complexes, guanidinium or bisguanidinium, as well as mitochondria-targeting cancer therapies including PDT, PTT, CDT, and others are summarized. This review aims to furnish researchers with deep insights and hints in the design and applications of novel mitochondria-targeting agents for cancer therapy.
Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1–6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7–17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.
Currently, photosensitizers (PSs) that are microenvironment responsive and hypoxia active are scarcely available and urgently desired for antitumor photodynamic therapy (PDT). Presented herein is the design of a redox stimuli activatable metal‐free photosensitizer (aPS), also functioning as a pre‐photosensitizer as it is converted to a PS by the mutual presence of glutathione (GSH) and hydrogen peroxide (H2O2) with high specificity on a basis of domino reactions on the benzothiadiazole ring. Superior to traditional PSs, the activated aPS contributed to efficient generation of reactive oxygen species including singlet oxygen and superoxide ion through both type 1 and type 2 pathways, alleviating the aerobic requirement for PDT. Equipped with a triphenylphosphine ligand for mitochondria targeting, mitoaPS showed excellent phototoxicity to tumor cells with low light fluence under both normoxic and hypoxic conditions, after activation by intracellular GSH and H2O2. The mitoaPS was also compatible to near infrared PDT with two photon excitation (800 nm) for extensive bioapplications.
Mitochondria are the powerhouse of cells. They are vital organelles that maintain cellular function and metabolism. Dysfunction of mitochondria results in various diseases with a great diversity of clinical appearances. In the past, strategies have been developed for fabricating subcellular‐targeting drug‐delivery nanocarriers, enabling cellular internalization and subsequent organelle localization. Of late, innovative strategies have emerged for the smart design of multifunctional nanocarriers. Hierarchical targeting enables nanocarriers to evade and overcome various barriers encountered upon in vivo administration to reach the organelle with good bioavailability. Stimuli‐responsive nanocarriers allow controlled release of therapeutics to occur at the desired target site. Synergistic therapy can be achieved using a combination of approaches such as chemotherapy, gene and phototherapy. In this Review, we survey the field for recent developments and strategies used in the smart design of nanocarriers for mitochondria‐targeted therapeutics. Existing challenges and unexplored therapeutic opportunities are also highlighted and discussed to inspire the next generation of mitochondrial‐targeting nanotherapeutics.
An optical-resolution photoacoustic microscope (OR-PAM) with capability of fast axial-scanning was developed by using a tunable acoustic gradient (TAG) lens. The TAG lens was designed to continuously changing the focal plane of OR-PAM by modulating its refractive power with fast-changing ultrasonic standing wave. The performance was shown by imaging a carbon fiber. We achieved a DoF of about 750 μm. The head of a zebrafish was also imaged to further demonstrate the feasibility of our method.
Ag2S nanoparticles are increasingly important in biomedicine such as cancer imaging. However, there is only limited success in the exploration of theranostic Ag2S nanoparticles for photo-induced cancer imaging and simultaneous therapy. Here, we report size-dependent Ag2S nanodots with well-defined nanostructure as a theranostic agent for multimodal imaging and simultaneous photothermal therapy, which are precisely synthesized through precisely controlled growth of Ag2S in hollow human serum albumin nanocages. These nanodots produce effective fluorescence in second near-infrared (NIR-II) region, distinct photoacoustic intensity, and good photothermal conversion in a size-dependent manner under light irradiation, thereby generating the sufficient in vivo fluorescent and photoacoustic signals, as well as potent hyperthermia at tumors. Moreover, Ag2S nanodots possess ideal resistance to photo-bleaching, effective cellular uptake, preferable tumor accumulation, as well as in vivo elimination, thus facilitating NIR-II fluorescence/photoacoustics imaging with both ultra-sensitivity and microscopically spatial resolution, and simultaneous photothermal tumor ablation. These findings provide the insights of clinically potential Ag2S nanodots for cancer theranostics.
Polymer encapsulated organic nanoparticles have recently attracted increasing attention in the biomedical field because of their unique optical properties, easy fabrication and outstanding performance as imaging and therapeutic agents. Of particular importance is the polymer encapsulated nanoparticles containing conjugated polymers (CP) or fluorogens with aggregation induced emission (AIE) characteristics as the core, which have shown significant advantages in terms of tunable brightness, superb photo- and physical stability, good biocompatibility, potential biodegradability and facile surface functionalization. In this review, we summarize the latest advances in the development of polymer encapsulated CP and AIE fluorogen nanoparticles, including preparation methods, material design and matrix selection, nanoparticle fabrication and surface functionalization for fluorescence and photoacoustic imaging. We also discuss their specific applications in cell labeling, targeted in vitro and in vivo imaging, blood vessel imaging, cell tracing, inflammation monitoring and molecular imaging. We specially focus on strategies to fine-tune the nanoparticle property (e.g. size and fluorescence quantum yield) through precise engineering of the organic cores and careful selection of polymer matrices. The review also highlights the merits and limitations of these nanoparticles as well as strategies used to overcome the limitations. The challenges and perspectives for the future development of polymer encapsulated organic nanoparticles are also discussed.
Nanorobotic manipulation to access subcellular organelles remains unmet due to the challenge in achieving intracellular controlled propulsion. Intracellular organelles, such as mitochondria, are an emerging therapeutic target with selective targeting and curative efficacy. We report an autonomous nanorobot capable of active mitochondria-targeted drug delivery, prepared by facilely encapsulating mitochondriotropic doxorubicin-triphenylphosphonium (DOX-TPP) inside zeolitic imidazolate framework-67 (ZIF-67) nanoparticles. The catalytic ZIF-67 body can decompose bioavailable hydrogen peroxide overexpressed inside tumor cells to generate effective intracellular mitochondriotropic movement in the presence of TPP cation. This nanorobot-enhanced targeted drug delivery induces mitochondria-mediated apoptosis and mitochondrial dysregulation to improve the in vitro anticancer effect and suppression of cancer cell metastasis, further verified by in vivo evaluations in the subcutaneous tumor model and orthotopic breast tumor model. This nanorobot unlocks a fresh field of nanorobot operation with intracellular organelle access, thereby introducing the next generation of robotic medical devices with organelle-level resolution for precision therapy.
Bioluminescence (BL) imaging has emerged to tackle the potential challenges of fluorescence (FL) imaging including the autofluorescence background, inhomogeneous illumination over a wide imaging field, and the light-induced overheating effect. Taking advantage of the bioluminescence resonance energy transfer (BRET) mechanism between a conventional luciferin compound and a suitable acceptor, the visible light of the former can be extended to photons with longer wavelengths emitting from the latter. Although BRET-based self-illuminating imaging probes have already been prepared, employing potentially cytotoxic elements as the acceptor with the emission wavelengths which hardly reach the first near-infrared (NIR-I) window, has limited their applications as safe and high performance in vivo imaging agents. Herein, we report a biocompatible, self-illuminating, and second near-infrared (NIR-II) emissive probe to address the cytotoxicity concerns as well as improve the penetration depth and spatiotemporal resolution of BL imaging. To this end, NanoLuc luciferase enzyme molecules were immobilized on the surface of silver sulfide quantum dots to oxidize its luciferin substrate and initiate a single-step BRET mechanism, resulting in NIR-II photons from the quantum dots. The resulting dual modality (BL/FL) probes were successfully applied to in vivo tumor imaging in mice, demonstrating that NIR-II BL signals could be easily detected from the tumor sites, giving rise to ∼2 times higher signal-to-noise ratios compared to those obtained under FL mode. The results indicated that nontoxic NIR-II emitting nanocrystals deserve more attention to be tailored to fill the growing demands of preparing appropriate agents for high quality BL imaging.
Although Type I photosensitizers with aggregation-induced emission (AIE) characteristics have thrived as alternative tools for cancer photodynamic therapy (PDT) thanks to their efficient reactive oxygen species (ROS) generation and hypoxia resistance, accumulated reducing substances sinside the tumor and the short lifespan of ROS limit their therapeutic effects. How to continuously generate long-lasting ROS in tumors remains a thorny problem. Herein, we constructed an uninterrupted ROS generator by incorporating the H2S donor, (NH4)2S, and a Type I AIE photosensitizer, TDCAc, into an injectable agarose hydrogel, namely TSH. Mitochondria-targeting TDCAc exhibited excellent performance in multi-model Type I photodynamic/photothermal therapy under near-infrared laser irradiation. While (NH4)2S generates H2S gas in the acidic tumor microenvironment upon photothermal dissolution of TSH gel, which diffuses into cancer cells and effectively inhibits intracellular catalase activity. Thus, the intrinsic H2O2 consumption pathway is blocked to promote endogenous labile iron pool-mediated continuous hydroxyl radical (·OH) generation in tumors. In both in vitro and in vivo experiments, uninterrupted massive production of·OH in cancer cells after laser irradiation of TSH gels was demonstrated. Notably, H2S gas therapy is firstly combined with Type I AIE PDT, affording a novel synergistic strategy of continuous·OH generation for boosting tumor therapy.
Hydrogel dressings are highly biocompatible and can maintain a moist wound environment, suggesting constructing an efficient multi-modal antibacterial hydrogel platform is a promising strategy for treating bacterial wound infections. In this work, a composite Ag2S quantum dot/mSiO2 NPs hydrogel (NP hydrogel) with antibacterial ability was constructed by incorporating Ag2S quantum dots (QDs) modified by mesoporous silica (mSiO2) into the network structure of 3-(trimethoxylmethosilyl) propyl methacrylate based on free radical polymerization. The NP hydrogel showed outstanding controllable photothermal and photodynamic characteristics under 808 nm near infrared (NIR) light irradiation, with a photothermal conversion efficiency of 57.3%. Additionally, the release of Ag⁺ could be controlled by the inherent volume change of the NP hydrogel made of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) during NIR laser exposure, with the embedded Ag2S QDs working as a reservoir to release Ag⁺ continuously from the hydrogel matrix to achieve bactericidal activity. The synergetic effects between hyperthermia, radical oxygen species, and Ag⁺ released under NIR radiation endowed the NP hydrogel with prominent antibacterial properties against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA), with an inhibition rate of 99.7% and 99.8%, respectively. In vivo wound healing experiments indicated that the NP hydrogel could enhance bacterial clearance, increase collagen coverage area and up-regulate VEGF expression, exhibiting high biocompatibility. Overall, this study proposed an efficient and highly biocompatible multi-modal therapeutic nanohydrogel, opening up a new way for developing broad-spectrum antibacterial wound dressings to treat bacterial wound infections.
Statement of significance
Bacterial wound infection is still one of the most difficult medical problems. In this work, a stimulating NIR-responsive hydrogel encapsulating functional Ag2S QDs was prepared, which showed high photothermal conversion efficiency (57.3%) and outstanding antibacterial ability under 808 nm NIR laser, killing 99.7% and 99.8% of E. coli and MRSA in 4 min, respectively. During NIR light irradiation, the release rate of Ag⁺ could be regulated by the intrinsic volume transition of the hydrogel, leading to remarkable antibacterial properties in vitro and in vivo under the combined action of hyperthermia, radical oxygen species and Ag⁺ released. This study proposed a novel multi-modal therapeutic nanohydrogel, opening up a new way for developing broad-spectrum antibacterial wound dressings to treat bacterial wound infections.
A nanoplatform based on Ag2S quantum dots (QDs) and tellurium nanorods (TeNRs) was developed for combined chemo-photothermal therapy guided by H2O2-activated near-infrared (NIR)-II fluorescence imaging. Polypeptide PC10AGRD-modified TeNRs and Ag2S QDs were co-encapsulated in 4T1 cell membrane to prepare a nanoplatform ([email protected]). Ag2S QDs and TeNRs in the [email protected] were used as a fluorescence probe and photosensitizer, and a chemotherapeutic prodrug and quenching agent to quench the fluorescence of Ag2S QDs, respectively. After the [email protected] was specifically targeted to the tumor site, the TeNRs were dissolved by the high concentration of H2O2 at the tumor site to light up the fluorescence of Ag2S QDs for NIR-II fluorescence imaging. In addition, the generated toxic TeO6⁶⁻ molecules decreased ATP production by selective cancer chemotherapy, which is beneficial for photothermal therapy. The elevated temperature due to photothermal therapy in turn promoted the chemical reaction in chemotherapy. In vitro and in vivo toxicity results showed that the [email protected] possesses high biocompatibility. Compared to single photothermal therapy and chemotherapy, the synergistic chemo-photothermal therapy can effectively suppress the growth of 4T1 tumor. This all-in-one nanoplatform provides a boulevard for the combination therapy of tumors guided by NIR-II fluorescence imaging.
Statement of significance
: NIR-II fluorescence imaging shows the characteristics of low tissue absorption, reflection, and scattering, which can greatly reduce the influence of autofluorescence in vivo. However, the non-negligible effect of autofluorescence is still observed in fluorescence imaging in vivo. Therefore, there is an urgent need to develop a strategy of controlled release of fluorescence for accurate imaging and tumor therapy. Here, Ag2S quantum dots (QDs) with NIR-II fluorescence emission and good photothermal conversion efficiency are used as a fluorescence probe and photosensitizer, and tellurium nanorods (TeNRs) are used as a chemotherapeutic prodrug and quenching agent to quench the fluorescence of Ag2S QDs. This multiple nanoplatform provides an inspiration for the combination therapy of tumor guided by NIR-II fluorescence imaging.
Infiltration of inflammatory cells, especially the M1 macrophages that secrete various types of inflammation cytokines, play crucial roles in the pathogenesis of rheumatoid arthritis (RA). To relief synovial inflammation, M1 macrophages must be eliminated or switched to anti-inflammatory M2 phenotype. We herein developed folic acid modified silver nanoparticles (FA-AgNPs) that can actively deliver into M1 macrophages to synergistically induce M1 macrophages reduction and M2 macrophages polarization for effective RA treatment. The AgNPs was facilely prepared, PEGylated and modified with FA to realize M1 macrophages targeting delivery via folate receptor overexpressed on M1 macrophages surface. After entering cells, FA-AgNPs dissolved and released Ag+ in response to intracellular glutathione (GSH), which is the key element to exert a series of anti-inflammatory functions, such as M1 macrophages apoptosis and reactive oxygen species (ROS) scavenging to facilitate M2 macrophages polarization, both of which contributed to RA treatment. This nano-system could passively accumulate into inflamed joints, permit potent anti-inflammatory activity, and impose strong therapeutic efficacy in mice RA models with high biosafety. After treatment, FA-AgNPs could be gradually cleared from the body mainly via feces without tissue accumulation, and did not show any appreciable long-term toxicity. This work declares the first example of using bio-active nanoparticles for RA treatment without loading any drugs, and highlights the potential of FA-AgNPs for targeted RA therapy via simultaneous M1 macrophage apoptosis and M1-to-M2 macrophages re-polarization.
Mitophagy is a specific self-protective autophagic process that degrades damaged or dysfunctional mitochondria, and is generally considered to reduce the effectiveness of mitochondria-targeted therapies. Here, we report an energy depletion-based anticancer strategy by selectively activating excessive mitophagy in cancer cells. We fabricate a type of mitochondria-targeting nanomicelles via the self-assembly of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dc-IR825 (a near-infrared cyanine dye and a photothermal agent). The TPGS/dc-IR825 nanomicelles enable mitochondrial damage in cancer cells, which, for self-protection, activate two autophagic pathways, (1) mitophagy and (2) adenosine triphosphate (ATP) shortage-triggered autophagy. However, the excessive mitophagy/autophagy activities far surpass the degradative capacity of autolysosomes, leading to the formation of micrometer-sized vacuoles and degradation blockage. Immunofluorescence staining and Western blot analysis reveal that the nanomicelle-treated cancer cells are under severe ATP shortage, which eventually causes substantial cell death. Moreover, the nanomicelles intravenously injected into tumor-bearing mice show high tumor accumulation, long tumor retention, and inhibit the tumor growth by inducing excessive mitophagy/autophagy and energy depletion in tumor cells. Additional near-infrared laser irradiation treatment further enhances the in vitro and in vivo anticancer efficiencies of the nanomicelles, due to the excellent photothermal and photodynamic effects of dc-IR825. We believe that this work highlights the important role of mitophagy/autophagy in treating cancers.
Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M-ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria-targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self-delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy.
A high yield quantum yield (4.3%) hybrid nanogel system based on engineered polypeptide and Ag2S quantum dot has been developed as multifunctional diagnostic and therapeutic agent for targeted second near-infrared...