Self-Adaptive Photodynamic-to-Photothermal Switch for Smart Antitumor Photoimmunotherapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess different merits in cancer phototherapy, but the tumor microenvironment becomes unfavorable during the phototheranostic progress. Herein, we report a self-adaptive cyanine derivative Cy5-TPA with the PDT-dominated state to PTT-dominated state autoswitch feature for enhanced photoimmunotherapy. The incorporation of rotatable triphenylamine (TPA) moiety renders Cy5-TPA with the temperature or intramolecular-motion regulated photoactivities, which shows preferable reactive oxygen species (ROS) generation at lower temperature while stronger photothermal conversion at higher ones. Such a promising feature permits the in situ switch from PDT-dominated state to PTT-dominated state along with intratumoral temperature increase during laser irradiation, which also works in line with the concurrently reduced intratumoral oxygen level, exhibiting a self-adaptive phototherapeutic behavior to maximize the phototherapeutic antitumor outcome. Most importantly, the self-adaptive PDT-dominated state to PTT-dominated state switch also facilitates the sequential generation and release of damage-associated molecular patterns during immunogenic cell death (ICD). Hence, Cy5-TPA demonstrates excellent photoimmunotherapy performance in ICD induction, dendritic cell maturation, and T cell activation for tumor eradication and metastasis inhibition.

Switchable Dual Circularly Polarized Luminescence in Through-Space Conjugated Chiral Foldamers.

Organic materials with switchable dual circularly polarized luminescence (CPL) are highly desired because they can not only directly radiate tunable circularly polarized light themselves but also induce CPL for guests by providing a chiral environment in self-assembled structures or serving as the hosts for energy transfer systems. However, most organic molecules only exhibit single CPL and it remains challenging to develop organic molecules with dual CPL. Herein, novel through-space conjugated chiral foldamers are constructed by attaching two biphenyl arms to the 9,10-positions of phenanthrene, and switchable dual CPL with opposite signs at different emission wavelengths are successfully realized in the foldamers containing high-polarizability substitutes (cyano, methylthiol and methylsulfonyl). The combined experimental and computational results demonstrate that the intramolecular through-space conjugation has significant contributions to stabilizing the folded conformations. Upon photoexcitation in high-polar solvents, strong interactions between the biphenyl arms substituted with cyano, methylthio or methylsulfonyl and the polar environment induce conformation transformation for the foldamers, resulting in two transformable secondary structures of opposite chirality, accounting for the dual CPL with opposite signs. These findings highlight the important influence of the secondary structures on the chiroptical property of the foldamers and pave a new avenue towards efficient and tunable dual CPL materials.

Free Radical-Mediated Photocyclization of Triphenylphosphindole Oxides for Photoactivated and Self-Reported Lipid Peroxidation.

Photocyclization is demonstrated as a powerful tool for building complicated polycyclic molecules. And efficient photocyclization is competent as an artful strategy to develop photo-responsive smart materials. Herein, an efficient free radical-mediated photocyclization for triphenylphosphindole oxide (TPPIO) derivatives to generate tribenzophosphindole oxide (TBPIO) derivatives at ambient condition is reported. The reaction mechanism and substituent effect on photocyclization efficiency are thoroughly investigated. Additionally, photophysical and photochemical properties of TPPIO and TBPIO derivatives are measured for comparison and deeply deciphered by theoretical calculation. TPPIO derivatives own typical aggregation-induced emission feature but barely generate reactive oxygen species (ROS), while TBPIO derivatives experience aggregation-caused quenching but show efficient Type I ROS generation capacity. Further, in vitro experiments demonstrate that this photo-conversion can efficiently occur in situ in living cells to activate photodynamic therapy (PDT) effect to trigger lipid peroxidation with selective fluorescence "light up" in lipid droplet area under continuous irradiation. This work extends the optoelectronically and biologically interesting phosphindole oxide-containing π-conjugated systems through an efficient synthetic strategy, provides in-depth mechanistic descriptions in the aspects of reaction and property, and further presents their great potentials for photoactivated and self-reported PDT.

In-situ electro-responsive through-space coupling enabling foldamers as volatile memory elements.

Voltage-gated processing units are fundamental components for non-von Neumann architectures like memristor and electric synapses, on which nanoscale molecular electronics have possessed great potentials. Here, tailored foldamers with furan‒benzene stacking (f-Fu) and thiophene‒benzene stacking (f-Th) are designed to decipher electro-responsive through-space interaction, which achieve volatile memory behaviors via quantum interference switching in single-molecule junctions. f-Fu exhibits volatile turn-on feature while f-Th performs stochastic turn-off feature with low voltages as 0.2 V. The weakened orbital through-space mixing induced by electro-polarization dominates stacking malposition and quantum interference switching. f-Fu possesses higher switching probability and faster responsive time, while f-Th suffers incomplete switching and longer responsive time. High switching ratios of up to 91 for f-Fu is realized by electrochemical gating. These findings provide evidence and interpretation of the electro-responsiveness of non-covalent interaction at single-molecule level and offer design strategies of molecular non-von Neumann architectures like true random number generator.

Combining PD-L1 blockade with immunogenic cell death induced by AIE photosensitizer to improve antitumor immunity.

Immunogenic cell death (ICD) is considered an effective death mode to trigger immune response. However, the currently available efficient ICD inducers are quite limited. Endoplasmic reticulum (ER) stress is known as the precursor of ICD, which can be directly triggered by reactive oxygen species in situ. Herein, a novel photosensitizer (α-Th-TPA-PIO) based on phosphindole oxide, featuring aggregation-induced emission (AIE) is designed and prepared, which possesses good ability of hydroxyl radicals (HO•) generation. Besides, α-Th-TPA-PIO can selectively accumulate in ER and trigger ER stress under white light irradiation, further leading to effective ICD. Combining with anti-programmed death-ligand 1 (anti-PD-L1), the synergistic effect of photodynamic therapy (PDT) and immune checkpoint blockade can achieve a significantly enhanced inhibition effect on the growth of tumors and simultaneously provoke a systemic antitumor immune response. Notably, by adopting this therapeutic strategy to bilateral and metastatic tumor models, the growth of both primary and distant subcutaneous tumors can be successfully suppressed, and metastatic tumor can also be inhibited to some degree. Taken together, this work not only provides a novel ICD photoinducer based on PDT, but also brings about a useful immunomodulatory strategy to realize superior antitumor effect.

Antibacterial Theranostic Agents with Negligible Living Cell Invasiveness: AIE-Active Cationic Amphiphiles Regulated by Alkyl Chain Engineering.

To address the threat of bacterial infection in the following post-antibiotic era, developing effective antibacterial approaches is of utmost urgency. Theranostic medicine integrating diagnosis and therapy is a promising protocol to fight against pathogenic bacteria. But numerous reported antibacterial theranostic materials are disclosed to be trapped in the excessive invasiveness to living mammal cells, leading to false positives and possible biosafety risks. Herein, a series of cationic pyridinium-substituted phosphindole oxide derivatives featuring aggregation-induced emission are designed, and alkyl chain engineering is conducted to finely tune their hydrophobicity and investigate their bioaffinity preference for living mammal cells and pathogenic bacteria. Most importantly, an efficient theranostic agent (PyBu-PIO) is acquired that is free from living cell invasiveness with negligible cytotoxicity and yet holds a good affinity for Gram-positive bacteria, including drug-resistant strains, with a superior inactivating effect. Externally applying PyBu-PIO onto Gram-positive bacteria-infected skin wounds can achieve creditable imaging effects and successfully accelerate the healing processes with reliable biosafety. This work proposes living cell invasiveness as a criterion for antibacterial theranostic materials and provides important enlightenment for the design of antibacterial theranostic materials.

A photoactivatable theranostic probe for simultaneous oxidative stress-triggered multi-color cellular imaging and photodynamic therapy.

Simultaneous in situ monitoring critical organelles upon oxidative stress and implementing therapeutics utilizing oxidative stress are of vital importance and remain challenging task. Herein, we rationally design and facilely synthesized a photoactivatable fluorescent probe bearing 1,4-dihydropyridine moiety with aggregation-induced emission (AIE) tendency, namely TPA-DHPy, which can rapidly transform into its pyridine counterpart TPA-Py via photo-oxidative dehydrogenation showing strong polarity sensitivity and largely red-shifted emission. TPA-DHPy- and TPA-Py-based type I/type II photosensitization is able to effectively generate reactive oxygen species to induce in situ oxidative stress under white light irradiation. TPA-DHPy can be taken up by cancer cells, and gradually light up lipid droplets (LDs) and endoplasmic reticulum (ER) during photoactivatable process, as well as in situ monitoring difference and alteration of their microenvironment upon oxidative stress by means of multi-color fluorescence imaging in lambda mode. Furthermore, the in situ generated TPA-Py is capable of further destroying the functions of LDs and ER with prolonging the irradiation time, and remarkably inhibiting tumor growth under white light irradiation by the way of photodynamic therapy. This study thus offers useful insights into designing a new generation of theranostic agents towards imaging-guided precise cancer therapy.

Cationization-Enhanced Type I and Type II ROS Generation for Photodynamic Treatment of Drug-Resistant Bacteria.

Photodynamic therapy as an emerging phototheranostic approach holds great potential for antibacterial treatment, but is limited by compromised reactive oxygen species (ROS) generation in an aggregate and hypoxic microenvironment. Herein, we report a molecular cationization approach to boost the ROS, especially type I ROS generation of aggregation-induced emission (AIE) photosensitizers for photodynamic treatment of drug-resistant bacteria. Such cationization reinforces the electron-accepting ability of the cationic moiety, promotes intersystem crossing (ISC), and increases electron separation and transfer processes. The resultant CTBZPyI exhibits largely enhanced ROS generation ability with predominant hydroxyl radical generation over its neutral counterpart in aggregate. Moreover, cationization also confers CTBZPyI with the bacterial binding ability and a moderate bacterial inactivation ability in the dark. Further light irradiation leads to superb antibacterial performance, which largely promotes the healing process of a MRSA-infected wound. Such a cationization strategy is expected to be a general strategy for the design of highly effective type I photosensitizers for bacterial infection treatment.

Achieving Multiple Quantum-Interfered States via Through-Space and Through-Bond Synergistic Effect in Foldamer-Based Single-Molecule Junctions.

The construction of multivalued logic circuits by multiple quantum-interfered states at the molecular level can make full use of molecular diversity and versatility, broadening the application of molecular electronics. Understanding charge transport through different conducting pathways and how they interact with each other in molecules with a secondary structure is an indispensable foundation to achieve this goal. Herein, we elucidate the synergistic effect from through-space and through-bond conducting pathways in foldamers derived from ortho-pentaphenylene by the separate modulation on these pathways. The shrinkage of central heterocycles' sizes allows foldamers to stack with larger overlap degrees, resulting in level-crossing and thus transformation from constructive quantum interference (CQI) to destructive quantum interference (DQI) in a through-space pathway. The alteration of central heterocycles' connection sites enhances through-bond conjugation, leading to amplified contribution from a through-bond pathway. The enhanced through-bond pathway destructively interferes with the through-space pathway, exerting a suppression effect on transmission. Therefore, four quantum-interfered states of through-space and through-bond combination are generated, including through-space CQI-dominated states, through-space DQI-dominated states, through-space CQI states with through-bond suppression, and through-space DQI states with through-bond suppression. These findings enable us to regulate charge transport within high-order structures via multiple conducting pathways and provide a proof of concept to construct multivalued logic circuits.

Effective Therapy of Drug-Resistant Bacterial Infection by Killing Planktonic Bacteria and Destructing Biofilms with Cationic Photosensitizer Based on Phosphindole Oxide.

Developing effective therapies to fight against biofilm-associated infection is extremely urgent. The complex environment of biofilm forces the bacteria to evade the elimination of antibiotics, resulting in recalcitrant chronic infections. To address this issue, a cationic antibacterial agent based on phosphindole oxide (ß-PM-PIO) is designed and prepared. The unique molecular structure endows ß-PM-PIO with aggregation-induced emission feature and efficient singlet oxygen generation ability. ß-PM-PIO shows excellent visual diagnostic function to planktonic bacteria and biofilm. In addition, owing to the synergistic effect of phototoxicity and dark toxicity, ß-PM-PIO can achieve superb antibacterial and antibiofilm performance against Gram-positive bacteria with less potential of developing drug resistance. Notably, ß-PM-PIO also holds excellent anti-infection capacity against drug-resistant bacteria in vivo with negligible side effects. This work offers a promising platform to develop advanced antibacterial agents against multidrug-resistant bacterial infection.

Through-Space Conjugated Electron Transport Materials for Improving Efficiency and Lifetime of Organic Light-Emitting Diodes.

Thermally stable electron transport (ET) materials with high electron mobility and high triplet state energy level are highly desired for the fabrication of efficient and stable organic light-emitting diodes (OLEDs). Herein, a new design strategy of constructing through-space conjugated folded configuration is proposed to explore robust ET materials, opposite to the widely used planar configuration. By bonding two quinolines to the 9,10-positions of phenanthrene, two novel folded molecules with high thermal and morphological stabilities and high triplet state energy levels (>2.7 eV) are created. These folded molecules possess excellent ET ability with electron mobilities of three orders of magnitude higher than those of linear and planar counterparts. Theoretical calculation and crystallography analysis demonstrate the through-space conjugated folded configuration has not only reduced reorganization energy but also enlarged charge transfer integral at various dimensions, bringing about efficient multi-dimensional ET, independent of molecular orientation. By adopting the folded molecule as ET layers, OLEDs with no matter delayed fluorescence or phosphorescence emitters can achieve high external quantum efficiencies and long operational lifetimes simultaneously. This work paves a new avenue towards robust ET materials to improve efficiency and stability of OLEDs.

Type I photosensitizers based on phosphindole oxide for photodynamic therapy: apoptosis and autophagy induced by endoplasmic reticulum stress.

Photodynamic therapy (PDT) is considered a pioneering and effective modality for cancer treatment, but it is still facing challenges of hypoxic tumors. Recently, Type I PDT, as an effective strategy to address this issue, has drawn considerable attention. Few reports are available on the capability for Type I reactive oxygen species (ROS) generation of purely organic photosensitizers (PSs). Herein, we report two new Type I PSs, α-TPA-PIO and ß-TPA-PIO, from phosphindole oxide-based isomers with efficient Type I ROS generation abilities. A detailed study on photophysical and photochemical mechanisms is conducted to shed light on the molecular design of PSs based on the Type I mechanism. The in vitro results demonstrate that these two PSs can selectively accumulate in a neutral lipid region, particularly in the endoplasmic reticulum (ER), of cells and efficiently induce ER-stress mediated apoptosis and autophagy in PDT. In vivo models indicate that ß-TPA-PIO successfully achieves remarkable tumor ablation. The ROS-based ER stress triggered by ß-TPA-PIO-mediated PDT has high potential as a precursor of the immunostimulatory effect for immunotherapy. This work presents a comprehensive protocol for Type I-based purely organic PSs and highlights the significance of considering the working mechanism in the design of PSs for the optimization of cancer treatment protocols.

Efficient Near-Infrared Photosensitizer with Aggregation-Induced Emission for Imaging-Guided Photodynamic Therapy in Multiple Xenograft Tumor Models.

Photodynamic therapy (PDT) strategy has been widely used in tumor treatment, and the reagents for reactive oxygen species (ROS) play a crucial role. Herein, we develop a fluorogen (TTB) containing an electron-accepting benzo[1,2-b:4,5-b']dithiophene 1,1,5,5-tetraoxide core and electron-donating 4,4'-(2,2-diphenylethene-1,1-diyl)bis(N,N-diphenylaniline) groups for image-guided targeting PDT application. TTB exhibits a prominent aggregation-induced emission (AIE) property with strong near-infrared (NIR) fluorescence in aggregates and is capable of efficiently generating ROS of O2•- and 1O2 under white light irradiation. The nanoparticles (RGD-4R-MPD/TTB NPs) with NIR emission (∼730 nm), high photostability, and low dark cytotoxicity are fabricated by encapsulating TTB within polymeric matrix and then modified with RGD-4R peptide. They show excellent performance in targeting PDT treatment of PC3, HeLa, and SKOV-3 cancer cells in vitro. The investigations on pharmacokinetics, biodistribution, and long-term tracing in vivo reveal that RGD-4R-MPD/TTB NPs can selectively accumulate in tumors for real-time, long-term image-guided PDT treatment. The RGD-4R-MPD/TTB NPs-mediated PDT in multiple xenograft tumor models disclose that the growth of cervical, prostate, and ovarian cancers in mice can be effectively inhibited. These results demonstrate that the reagents employing NIR fluorogen TTB as a photosensitizer could be promising candidates for in vivo image-guided PDT treatments of tumors.

Assembly of 1H-isoindole derivatives by selective carbon-nitrogen triple bond activation: access to aggregation-induced emission fluorophores for lipid droplet imaging.

A novel strategy has been established to assemble a series of single (Z)- or (E)-1H-isoindole derivatives through selectively and sequentially activating carbon-nitrogen triple bonds in a multicomponent system containing various nucleophilic and electrophilic sites. The reaction provides efficient access to structurally unique fluorophores with aggregation-induced emission characteristics. These new fluorophores show fluorescence wavelengths and efficiencies that can be modulated and have excellent potential to specifically light up lipid droplets (LDs) in living cells with bright fluorescence, low cytotoxicity and better photostability than commercially available LD-specific dyes.

Through-Space Conjugation: An Effective Strategy for Stabilizing Intramolecular Charge-Transfer States.

Intramolecular charge transfer (ICT) has significant impacts on organic optoelectronic materials, photochemistry, biotechnology, and so on. However, it is hard to stabilize the ICT state because of the rapid nonradiative charge recombination process, which often quenches light emission. In this work, we use new foldamers of the protonated pyridine-modified tetraphenylethene derivatives that possess through-space conjugation (TSC) characters as the models to study the impact of TSC on the ICT state. Steady and transient spectroscopies illustrate that the lifetime of the ICT state in the molecule with strong TSC can be much longer than those of molecules without TSC, giving rise to a higher fluorescence quantum yield. By combining the theoretical calculations, we demonstrate that the strong TSC can stabilize the ICT state and slow the charge recombination rate by more efficiently dispersing charges. This is a conceptually new design strategy for functional optoelectronic materials that require more stable ICT states.

Photostable and biocompatible AIE-active conjugated polyelectrolytes for efficient heparin detection and specific lysosome labelling.

A series of new conjugated polyelectrolytes (CPEs) with emissive tetraphenylethene-containing backbones and specific targeting pendants are synthesized and characterized. These new CPEs exhibit prominent aggregation-induced emission (AIE) properties, high photostability and low cytotoxicity, and can efficiently detect heparin and stain lysosomes in living cells.

Highly Efficient Nondoped OLEDs with Negligible Efficiency Roll-Off Fabricated from Aggregation-Induced Delayed Fluorescence Luminogens.

Purely organic emitters that can efficiently utilize triplet excitons are highly desired to cut the cost of organic light-emitting diodes (OLEDs), but most of them require complicated doping techniques for their fabrication and suffer from severe efficiency roll-off. Herein, we developed novel luminogens with weak emission and negligible delayed fluorescence in solution but strong emission with prominent delayed components upon aggregate formation, giving rise to aggregation-induced delayed fluorescence (AIDF). The concentration-caused emission quenching and exciton annihilation are well-suppressed, which leads to high emission efficiencies and efficient exciton utilization in neat films. Their nondoped OLEDs provide excellent electroluminescence efficiencies of 59.1 cd A-1 , 65.7 lm W-1 , and 18.4 %, and a negligible current efficiency roll-off of 1.2 % at 1000 cd m-2 . Exploring AIDF luminogens for the construction of nondoped OLEDs could be a promising strategy to advance device efficiency and stability.

Synthesis, aggregation-enhanced emission, polymorphism and piezochromism of TPE-cored foldamers with through-space conjugation.

A series of new folded tetraphenylethene derivatives with different substituents are stereoselectively synthesized, which exhibit interesting through-space conjugation, aggregation-enhanced emission, polymorphism and piezochromism properties.