A Light-Triggered J-Aggregation-Regulated Therapy Conversion: from Photodynamic/Photothermal Therapy to Long-Lasting Chemodynamic Therapy for Effective Tumor Ablation.

Reactive oxygen species (ROS) have become an effective tool for tumor treatment. The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) takes advantage of various ROS and enhances therapeutic effects. However, the activation of CDT usually occurs before PDT, which hinders the sustained maintenance of hydroxyl radicals (⋅OH) and reduces the treatment efficiency. Herein, we present a light-triggered nano-system based on molecular aggregation regulation for converting cancer therapy from PDT/photothermal therapy (PTT) to a long-lasting CDT. The ordered J-aggregation enhances the photodynamic properties of the cyanine moiety while simultaneously suppressing the chemodynamic capabilities of the copper-porphyrin moiety. Upon light irradiation, Cu-PCy JNPs demonstrate strong photodynamic and photothermal effects. Meanwhile, light triggers a rapid degradation of the cyanine backbone, leading to the destruction of the J-aggregation. As a result, a long-lasting CDT is sequentially activated, and the sustained generation of ⋅OH is observed for up to 48 hours, causing potent cellular oxidative stress and apoptosis. Due to their excellent tumor accumulation, Cu-PCy JNPs exhibit effective in vivo tumor ablation through the converting therapy. This work provides a new approach for effectively prolonging the chemodynamic activity in ROS-based cancer therapy.

Sulfonated Perylene as Three-in-One STING Agonist for Cancer Chemo-Immunotherapy.

Activation of stimulator of interferon genes (STING) by cyclic dinucleotides (CDNs) has been considered as a powerful immunotherapy strategy. While promising, the clinical translation of CDNs is still overwhelmed by its limited biostability and the resulting systemic immunotoxicity. Being differentiating from current application of exogenous CDNs to address these challenges, we herein developed one perylene STING agonist PDIC-NS, which not only promotes the production of endogenous CDNs but also inhibits its hydrolysis. More significantly, PDIC-NS can well reach lung-selective enrichment, and thus mitigates the systemic immunotoxicity upon intravenous administration. As a result, PDIC-NS had realized remarkable in vivo antitumor activity, and backward verified on STING knock out mice. Overall, this study states that PDIC-NS can function as three-in-one small-molecule STING agonist characterized by promoting the content and biostability of endogenous CDNs as well as possessing good tissue specificity, and hence presents an innovative strategy and platform for tumor chemo-immunotherapy.

A Terrylene-Anthraquinone Dyad as a Chromophore for Photothermal Therapy in the NIR-II Window.

A terrylenedicarboximide-anthraquinone dyad, FTQ, with absorption in the second near-infrared region (NIR-II) is obtained as a high-performance chromophore for photothermal therapy (PTT). The synthetic route proceeds by C-N coupling of amino-substituted terrylenedicarboximide (TMI) and 1,4-dichloroanthraquinone followed by alkaline-promoted dehydrocyclization. FTQ with extended π-conjugation exhibits an optical absorption band peaking at 1140 nm and extending into the 1500 nm range. Moreover, as determined by dielectric spectroscopy in dilute solutions, FTQ achieves an ultrastrong dipole moment of 14.4 ± 0.4 Debye due to intense intramolecular charge transfer. After encapsulation in a biodegradable polyethylene glycol (DSPE-mPEG2000), FTQ nanoparticles (NPs) deliver a high photothermal conversion efficiency of 49% under 1064 nm laser irradiation combined with excellent biocompatibility, photostability, and photoacoustic imaging capability. In vitro and in vivo studies reveal the great potential of FTQ NPs in photoacoustic-imaging-guided photothermal therapy for orthotopic liver cancer treatment in the NIR-II window.

NIR-II Perylene Monoimide-Based Photothermal Agent with Strengthened Donor-Acceptor Conjugation for Deep Orthotopic Glioblastoma Phototheranostics.

Extensive efforts have been devoted to the design of organic photothermal agents (PTAs) that absorb in the second near-infrared (NIR-II) bio-window, which can provide deeper tissue penetration that is significant for phototheranostics of lethal brain tumors. Herein, the first example of NIR-II-absorbing small organic molecule (N1) derived from perylene monoamide (PMI) and its bio-application after nano-encapsulation of N1 to function as a nano-agent for phototheranostics of deep orthotopic glioblastoma (GBM) is reported. By adopting a dual modification strategy of introducing a donor-acceptor unit and extending π-conjugation, the obtained N1 can absorb in 1000-1400 nm region and exhibit high photothermal conversation due to the apparent intramolecular charge transfer (ICT). A choline analogue, 2-methacryloyloxyethyl phosphorylcholine, capable of interacting specifically with receptors on the surface of the blood-brain barrier (BBB), is used to fabricate the amphiphilic copolymer for the nano-encapsulation of N1. The obtained nanoparticles demonstrate efficient BBB-crossing due to the receptor-mediated transcytosis as well as the small nanoparticle size of approximately 26 nm. The prepared nanoparticles exhibit excellent photoacoustic imaging and significant growth inhibition of deep orthotopic GBM. The current study demonstrates the enormous potential of PMI-based NIR-II PTAs and provides an efficient phototheranostic paradigm for deep orthotopic GBM.

Recent Advances in Nanoparticle-Mediated Co-Delivery System: A Promising Strategy in Medical and Agricultural Field.

Drug and gene delivery systems mediated by nanoparticles have been widely studied for life science in the past decade. The application of nano-delivery systems can dramatically improve the stability and delivery efficiency of carried ingredients, overcoming the defects of administration routes in cancer therapy, and possibly maintaining the sustainability of agricultural systems. However, delivery of a drug or gene alone sometimes cannot achieve a satisfactory effect. The nanoparticle-mediated co-delivery system can load multiple drugs and genes simultaneously, and improve the effectiveness of each component, thus amplifying efficacy and exhibiting synergistic effects in cancer therapy and pest management. The co-delivery system has been widely reported in the medical field, and studies on its application in the agricultural field have recently begun to emerge. In this progress report, we summarize recent progress in the preparation and application of drug and gene co-delivery systems and discuss the remaining challenges and future perspectives in the design and fabrication.

Perylenemonoimide-Based Colorimetric Probe with High Contrast for Naked-Eye Detection of Fluoride Ions.

Excessive fluoride ions (F-) in drinking water are harmful to the environment and human health. However, most reported probes of F- can only detect fluorocarbons rather than aqueous F-. Herein, a colorimetric and fluorescent probe (PMI-OH) based on perylenemonoimide is designed and synthesized for the detection of aqueous F-, with high sensitivity, good selectivity, and reversibility. The F- causes deprotonation of PMI-OH, leading to a significant red shift of 222 nm (from 520 to 742 nm) of the absorption band. Upon the addition of fluorocarbons, the fluorescence intensities of PMI-OH show good linearity against the concentrations of F-, realizing the quantitative detection of fluorocarbons with a limit of detection as low as 0.495 µM. Finally, PMI-OH is applied to detect F- in drinking water. The color of PMI-OH solution shows remarkable response from pink to green when the concentrations of F- exceed the upper limit set by the World Health Organization (WHO), realizing rapid and naked-eye detection of aqueous F-.

Construction and application of star polycation nanocarrier-based microRNA delivery system in Arabidopsis and maize.

BACKGROUND: MicroRNA (miRNA) plays vital roles in the regulation of both plant architecture and stress resistance through cleavage or translation inhibition of the target messenger RNAs (mRNAs). However, miRNA-induced gene silencing remains a major challenge in vivo due to the low delivery efficiency and instability of miRNA, thus an efficient and simple method is urgently needed for miRNA transformation. Previous researches have constructed a star polycation (SPc)-mediated transdermal double-stranded RNA (dsRNA) delivery system, achieving efficient dsRNA delivery and gene silencing in insect pests. RESULTS: Here, we tested SPc-based platform for direct delivery of double-stranded precursor miRNA (ds-MIRNA) into protoplasts and plants. The results showed that SPc could assemble with ds-MIRNA through electrostatic interaction to form nano-sized ds-MIRNA/SPc complex. The complex could penetrate the root cortex and be systematically transported through the vascular tissue in seedlings of Arabidopsis and maize. Meanwhile, the complex could up-regulate the expression of endocytosis-related genes in both protoplasts and plants to promote the cellular uptake. Furthermore, the SPc-delivered ds-MIRNA could efficiently increase mature miRNA amount to suppress the target gene expression, and the similar phenotypes of Arabidopsis and maize were observed compared to the transgenic plants overexpressing miRNA. CONCLUSION: To our knowledge, we report the first construction and application of star polycation nanocarrier-based platform for miRNA delivery in plants, which explores a new enable approach of plant biotechnology with efficient transformation for agricultural application.

Visualization of the process of a nanocarrier-mediated gene delivery: stabilization, endocytosis and endosomal escape of genes for intracellular spreading.

Nanoparticles have been widely applied as gene carrier for improving RNA interference (RNAi) efficiency in medical and agricultural fields. However, the mechanism and delivery process of nanoparticle-mediated RNAi is not directly visualized and elucidated. Here we synthesized a star polymer (SPc) consisted of a hydrophilic shell with positively-charged tertiary amine in the side chain, which was taken as an example to investigate the mechanism in gene delivery. The SPc could assemble with dsRNA spontaneously through electrostatic force, hydrogen bond and van der Waals force. Interestingly, the SPc could protect dsRNA from degradation by RNase A and insect hemolymph, thus remarkably increasing the stability of dsRNA. Meanwhile, the SPc could efficiently promote the cellular uptake and endosomal escape for intracellular spreading of dsRNA. Transcriptome analysis revealed that the SPc could up-regulate some key genes such as Chc, AP2S1 and Arf1 for activating clathrin-mediated endocytosis. Furthermore, the suppression of endocytosis hindered the cellular uptake of SPc-delivered dsRNA in vitro, and the subsequent RNAi effect was also disappeared in vivo. To our knowledge, our study is the first direct visualization of the detailed cellular delivery process and mechanism of nanocarrier-mediated gene delivery. Above mechanism supports the application of nanocarrier-based RNAi in gene therapy and pest management.

Chronic exposure to the star polycation (SPc) nanocarrier in the larval stage adversely impairs life history traits in Drosophila melanogaster.

BACKGROUND: Nanomaterials are widely used as pesticide adjuvants to increase pesticide efficiency and minimize environmental pollution. But it is increasingly recognized that nanocarrier is a double-edged sword, as nanoparticles are emerging as new environmental pollutants. This study aimed to determine the biotoxicity of a widely applied star polycation (SPc) nanocarrier using Drosophila melanogaster, the fruit fly, as an in vivo model. RESULTS: The lethal concentration 50 (LC50) value of SPc was identified as 2.14 g/L toward third-instar larvae and 26.33 g/L for adults. Chronic exposure to a sub lethal concentration of SPc (1 g/L) in the larval stage showed long-lasting adverse effects on key life history traits. Exposure to SPc at larval stage adversely impacted the lifespan, fertility, climbing ability as well as stresses resistance of emerged adults. RNA-sequencing analysis found that SPc resulted in aberrant expression of genes involved in metabolism, innate immunity, stress response and hormone production in the larvae. Orally administrated SPc nanoparticles were mainly accumulated in intestine cells, while systemic responses were observed. CONCLUSIONS: These findings indicate that SPc nanoparticles are hazardous to fruit flies at multiple levels, which could help us to develop guidelines for further large-scale application.

Nanocarrier-Loaded Imidaclothiz Promotes Plant Uptake and Decreases Pesticide Residue.

There is a great demand for improving the effective utilization of pesticides and reducing their application for sustainable agriculture, and polymeric nanoparticles have provided strong technical support for the efficient delivery of pesticides. To this context, we tried to construct a relatively safe imidaclothiz nano-delivery system for enhanced plant uptake, reduced pesticide residue and improved bioactivity toward green peach aphids. The imidaclothiz could be assembled with the hydrophobic core of SPc through hydrophobic association, which led to the self-assembly of nanoscale imidaclothiz/SPc complex consisting of nearly spherical particles. The SPc decreased the contact angle of imidaclothiz drops and remarkably increased the plant uptake. Furthermore, the bioactivity and control efficacy of imidaclothiz were significantly improved with the help of SPc in both laboratory and field. Excitingly, the residue of imidaclothiz decreased with the help of SPc 7 d after the treatment due to the faster degradation of nanoscale imidaclothiz/SPc complex, which exhibited no negative effects on agronomic traits of tobacco plants. The current study successfully constructed a nano-delivery system for imidaclothiz, which can not only increase the effective utilization of pesticides, but also decrease the pesticide residue.

Chirality of Perylene Diimides: Design Strategies and Applications.

Chirality is a particularly important concept in nature and exists at all length scales, ranging from the molecular level to the supramolecular level. Over the last two decades, various design strategies have been developed to construct chiral materials based on perylene diimides (PDIs) and to mimic the chiral assembly process in biological systems, but applications of these chiral aggregates are still at an early stage. This Minireview summarizes recent progress in the synthesis and properties of chiral PDIs. The chirality in PDI-based materials can be generated by three different approaches: from the twisted planes of PDIs, the chiral substituents of PDIs, and the co-assembly of achiral PDIs and chiral guests. A comprehensive understanding of the applications of chiral PDIs as well as potential future developments is also provided.

Photoregulated Morphological Transformation of Spiropyran Derivatives Achieving the Tunability of Interfacial Hydrophilicity.

Regulation of self-assembly morphology is an effective strategy to obtain advanced functional materials with expected properties. However, achieving remarkable morphological transformation by light irradiation is still a challenge. Herein, three simple spiropyran derivatives (SP1, SP2, and SP3) are constructed, achieving different degrees of morphological transformation from nanospheres to hollow tadpole-like structures (SP3), tubular structures (SP2), and microsheets (SP1) after ultraviolet light irradiation. Interestingly, the hollow tadpole-like structures (SP3) can further extend to Y-shaped or T-shaped tubular morphology. In the process, SP1, SP2, and SP3 can be isomerized from a closed-ring form (hydrophobicity) to an open-ring form (hydrophilicity) in different degrees, interacting differently with methanol solvent molecules. The formation of hollow structures or microsheets along with the isomerization of spiropyran derivatives contributes to the adjustment of the hydrophilicity of the interface. Therefore, SP1, SP2, and SP3 with photoregulated morphological transformation show promising applications in tunable interface materials.

From Dyestuff Chemistry to Cancer Theranostics: The Rise of Rylenecarboximides.

Fighting cancer with the means of chemistry remains a tremendous challenge and defines a pressing societal need. Compounds based on synthetic organic dyes have long been recognized as vital tools for cancer diagnosis and therapy (theranostics). Fluorescence and photoacoustic imaging of cancer as well as cancer treatment protocols such as photodynamic and photothermal therapy are all photobased technologies that require chromophores. However, a serious drawback of most chromophoric molecules is photobleaching over the course of their use in biological environments, which severely compromises the desired theranostic effects. At this point, rylenecarboximide (RI) dyes with ultrahigh photostability hold enormous promise. RI stands for a homologous series of dyes consisting of an aromatic core and carboximide auxochromic groups. They possess high molar extinction coefficients and finely tunable photophysical properties. RIs such as perylenebiscarboxylic acid monoimide (PMI), perylenetetracarboxylic acid diimide (PDI), terrylenetetracarboxylic acid diimide (TDI), and quaterrylene tetracarboxylic acid diimide (QDI) have attracted great scientific attention as colorants, components of organic photovoltaics and organic field-effect transistors, as well as tools for biological applications. PDI has appeared as one of the most widely studied RI dyes for fluorescence bioimaging. Our recent breakthroughs including chemotherapy with PDI-based DNA intercalators and photothermal therapy guided by photoacoustic imaging using PDI, TDI, or QDI, define urgent needs for further scientific research and clinical translation. In this Account, we tackle the relationship between chemical structures and photophysical and pharmacologic properties of RIs aiming at new contrast and anticancer agents, which then lay the ground for further biomedical applications. First, we introduce the design concepts for RIs with a focus on their structure-property relationships. Chemical structure has an enormous impact on the fluorescent, chemotoxic, photodynamic, and photothermal performance of RIs. Next, based on the resulting performance criteria, we employ RIs for fluorescence and photoacoustic cancer imaging as well as cancer therapies. When carrying electron donating substituents, PDIs and PMIs possess high fluorescence quantum yield and red-shifted emission which qualifies them for use in cancer fluorescence imaging. Also, some fluorescent PDIs are combined with chemodrugs or developed into DNA intercalators for chemotherapy. PDI-based photosensitizers are prepared by "heavy atom" substitution, showing potential for photodynamic therapy. Further, photothermal agents using PDI, TDI, and QDI with near-infrared absorption and excellent photothermal conversion efficiency offer high promise in photothermal cancer therapy monitored by photoacoustic imaging. Finally, looking jointly at the outstanding properties of RIs and the demands of current biomedicine, we offer an outlook toward further modifications of RIs as a powerful and practical platform for advanced cancer theranostics as well as treatment of other diseases.

Enzyme-Triggered Disassembly of Perylene Monoimide-based Nanoclusters for Activatable and Deep Photodynamic Therapy.

Photodynamic therapy (PDT) exhibits great potential for cancer therapy, but still suffers from nonspecific photosensitivity and poor penetration of photosensitizer. Herein, a smart perylene monoimide-based nanocluster capable of enzyme-triggered disassembly is reported as an activatable and deeply penetrable photosensitizer. A novel carboxylesterase (CE)-responsive tetrachloroperylene monoimide (P1) was synthesized and assembled with folate-decorated albumins into a nanocluster (FHP) with a diameter of circa 100 nm. Once P1 is hydrolyzed by the tumor-specific CE, FHP disassembles into ultrasmall nanoparticles (ca. 10 nm), facilitating the deep tumor penetration of FHP. Furthermore, such enzyme-triggered disassembly of FHP leads to enhanced fluorescence intensity (ca. 8-fold) and elevated singlet oxygen generation ability (ca. 4-fold), enabling in situ near-infrared fluorescence imaging and promoted PDT. FHP permits remarkable tumor inhibition in vivo with minimal side effects through imaging-guided, activatable, and deep PDT. This work confirms that this cascaded multifunctional control through enzyme-triggered molecular disassembly is an effective strategy for precise cancer theranostics.

Green-Light-Triggered Phase Transition of Azobenzene Derivatives toward Reversible Adhesives.

Studies on the azobenzene derivative based phase transitions mostly rely on photoisomerization, which require a long time to spontaneously revert back. Here we show a photothermal-driven solid-to-liquid transition and fast reversion of azobenzene derivatives. Owing to the aggregation of suitably substituted azobenzenes, solid-to-liquid transitions can be induced by photothermal effects under irradiation with green light. The liquid-state azobenzene derivatives spontaneously solidify again within 2 min due to heat release in a purely physical fashion. One thus obtains a perfectly reversible adhesion with a strength as high as that of commercial materials. Our work affords a novel concept to construct reversible adhesives via phase transitions of organic compounds induced by light.

Dually Cross-Linked Supramolecular Hydrogel as Surface Plasmon Resonance Sensor for Small Molecule Detection.

Dually cross-linked supramolecular hydrogels (DCSH) are designed to show responsive properties while maintaining the gel structure by introducing two different kinds of cross-links. This is realized by utilizing a photo-cross-linker for permanent cross-linking and ß-cyclodextrin (ß-CD) and ferrocene (Fc) as host-guest recognition pair. The DCSH shows increased swelling in the presence of the small target molecule adamantane amine (Ada). Ada can break the non-covalent bonding between ß-CD and Fc through competitive molecular guest interaction with ß-CD. By using a combination of surface plasmon resonance and optical waveguide spectroscopy, it is possible to use this behavior to construct a reversible sensor for specific small molecule detection.

A Water-Soluble, NIR-Absorbing Quaterrylenediimide Chromophore for Photoacoustic Imaging and Efficient Photothermal Cancer Therapy.

Precision phototheranostics, including photoacoustic imaging and photothermal therapy, requires stable photothermal agents. Developing such agents with high stability and high photothermal conversion efficiency (PTCE) remains a considerable challenge. Herein, we introduce a new photothermal agent based on water-soluble quaterrylenediimide (QDI) that can self-assemble into nanoparticles (QDI-NPs) in aqueous solution. Incorporating polyethylene glycol (PEG) into the QDI core significantly enhances both physiological stability and biocompatibility of QDI-NPs. The highly photostable QDI-NPs offer advantages including intense absorption in the near-infrared (NIR) and high PTCE of up to 64.7±4 %. This is higher than that of commercial indocyanine green (ICG). Their small size (ca. 10 nm) enables sustained retention in deep tumor sites and also proper clearance from the body. QDI-NPs allow high-resolution photoacoustic imaging and efficient 808 nm laser-triggered photothermal therapy of cancer in vivo.

Crystallization-Induced Emission Enhancement of a Deep-Blue Luminescence Material with Tunable Mechano- and Thermochromism.

Organic luminescent materials with the ability to reversibly switch the luminescence when subjected to external stimuli have attracted considerable interest in recent years. However, the examples of luminescent materials that exhibit multiresponsive properties are rarely reported. In this work, a new stimuli-responsive dye P1 is designed and synthesized with two identical chromophores of naphthalimide, one at each side of an amidoamine-based spacer. This amide-rich molecule offers many possibilities for forming intra- and intermolecular hydrogen bond interactions. Particularly, P1 has an intrinsic property of cocrystallizing with methanol. Compared with the pristine P1 sample, the as-prepared two-component cocrystalline material displays an exceptive deep-blue emission, which is extremely rare among naphthalimide-based molecules in the solid state. Furthermore, the target material exhibits an obvious mechanochromic fluorescent behavior and a large spectral shift under force stimuli. On the other hand, the cocrystalline material shows an unusual "turn off" thermochromic luminescence accompanied by solvent evaporation. Moreover, using external stimuli to reversibly manipulate fluorescent quantum yields is rarely reported to date. The results demonstrate the feasibility of a new design strategy for solid-state luminescence switching materials: the incorporation of solvents into organic compounds by cocrystallization to obtain a crystalline state luminescence system.

Novel magnetic-fluorescent bifunctional Janus nanofiber membrane.

Magnetic-fluorescent bifunctional materials have received global attention owing to their potential in many fields. Herein, we reported a novel magnetic-fluorescent bifunctional Janus nanofiber membrane (NFM) by adding the as-prepared magnetic CoFe2O4 nanoparticles into the polyacrylonitrile (PAN) side (m-PAN) and the fluorescent molecules of 1,8-naphthalene anhydride (1,8-NAD) into the polyvinylpyrrolidone (PVP) side (f-PVP) via electrospinning method. The obtained m-PAN/f-PVP Janus NFM exhibited excellent magnetic performance and high fluorescent properties due to the unique structure. Compared with the m-PAN/f-PVP composite NFM, the Janus NFM showed higher fluorescent performance because the fluorescent molecules were isolated from the magnetic nanoparticles. In addition, the Janus NFM not only maintain the good self-supporting state in water but also realize a directional movement attracted by a magnet. The unique structure of Janus nanofiber is of great importance and demonstrates great potential applications.

Visible Light-Induced Supra-Amphiphilic Switch Leads to Transition from Supramolecular Nanosphere to Nanovesicle Activated by Pillar[5]arene-Based Host-Guest Interaction.

A photoresponsive host-guest supramolecular complex (WP5⊃G) constructed by water-soluble pillar[5]arene (WP5) and spiropyran derivative (G) is presented. The spontaneous isomerization of G from spiropyran (SP) form to ring-opened merocyanine (MC) form happens either alone or in WP5⊃G in aqueous media. Irradiated by visible light, G can be converted into SP form completely and the hydrophilicity will be changed. G and WP5⊃G are both verified to self-assemble into nanospheres. Upon exposure to visible light, WP5⊃G reassemble into nanovesicles due to the change of supra-amphiphilicity, while G alone does not have this transition. Obviously, WP5 takes the key role that activates the photoinduced morphological transition.