Powerful Synergy of Traditional Chinese Medicine and Aggregation-Induced Emission-Active Photosensitizer in Photodynamic Therapy.

Breast cancer (BC) remains a significant global health challenge for women despite advancements in early detection and treatment. Isoliquiritigenin (ISL), a compound derived from traditional Chinese medicine, has shown potential as an anti-BC therapy, but its low bioavailability and poor water solubility restrict its effectiveness. In this study, we created theranostic nanoparticles consisting of ISL and a near-infrared (NIR) photosensitizer, TBPI, which displays aggregation-induced emission (AIE), with the goal of providing combined chemo- and photodynamic therapies (PDT) for BC. Initially, we designed an asymmetric organic molecule, TBPI, featuring a rotorlike triphenylamine as the donor and 1-methylpyridinium iodide as the acceptor, which led to the production of reactive oxygen species in mitochondria. We then combined TBPI with ISL and encapsulated them in DSPE-PEG-RGD nanoparticles to produce IT-PEG-RGD nanoparticles, which showed high affinity for BC, better intersystem crossing (ISC) efficiency, and Förster resonance energy transfer (FRET) between TBPI and ISL. In both 4T1 BC cell line and a 4T1 tumor-bearing BC mouse model, the IT-PEG-RGD nanoparticles demonstrated excellent drug delivery, synergistic antitumor effects, enhanced tumor-killing efficacy, and reduced drug dosage and side effects. Furthermore, we exploited the optical properties of TBPI with ISL to reveal the release process and distribution of nanoparticles in cells. This study provides a valuable basis for further exploration of IT-PEG-RGD nanoparticles and their anticancer mechanisms, highlighting the potential of theranostic nanoparticles in BC treatment.

Activation of Pyroptosis Using AIEgen-Based sp2 Carbon-Linked Covalent Organic Frameworks.

Covalent organic frameworks (COFs) have emerged as a promising class of crystalline porous materials for cancer phototherapy, due to their exceptional characteristics, including light absorption, biocompatibility, and photostability. However, the aggregation-caused quenching effect and apoptosis resistance often limit their therapeutic efficacy. Herein, we demonstrated for the first time that linking luminogens with aggregation-induced emission effect (AIEgens) into COF networks via vinyl linkages was an effective strategy to construct nonmetallic pyroptosis inducers for boosting antitumor immunity. Mechanistic investigations revealed that the formation of the vinyl linkage in the AIE COF endowed it with not only high brightness but also strong light absorption ability, long lifetime, and high quantum yield to favor the generation of reactive oxygen species for eliciting pyroptosis. In addition, the synergized system of the AIE COF and αPD-1 not only effectively eradicated primary and distant tumors but also inhibited tumor recurrence and metastasis in a bilateral 4T1 tumor model.

Dual Behavior Regulation: Tether-Free Deep-Brain Stimulation by Photothermal and Upconversion Hybrid Nanoparticles.

Optogenetics has been plagued by invasive brain implants and thermal effects during photo-modulation. Here, two upconversion hybrid nanoparticles modified with photothermal agents, named PT-UCNP-B/G, which can modulate neuronal activities via photostimulation and thermo-stimulation under near-infrared laser irradiation at 980 nm and 808 nm, respectively, are demonstrated. PT-UCNP-B/G emits visible light (410-500 nm or 500-570 nm) through the upconversion process at 980 nm, while they exhibit efficient photothermal effect at 808 nm with no visible emission and tissue damage. Intriguingly, PT-UCNP-B significantly activates extracellular sodium currents in neuro2a cells expressing light-gated channelrhodopsin-2 (ChR2) ion channels under 980-nm irradiation, and inhibits potassium currents in human embryonic kidney 293 cells expressing the voltage-gated potassium channels (KCNQ1) under 808-nm irradiation in vitro. Furthermore, deep-brain bidirectional modulation of feeding behavior is achieved under tether-free 980 or 808-nm illumination (0.8 W cm-2 ) in mice stereotactically injected with PT-UCNP-B in the ChR2-expressing lateral hypothalamus region. Thus, PT-UCNP-B/G creates new possibility of utilizing both light and heat to modulate neural activities and provides a viable strategy to overcome the limits of optogenetics.

Design of One-for-All Near-Infrared Aggregation-Induced Emission Nanoaggregates for Boosting Theranostic Efficacy.

Fluorescence-guided phototherapy, including photodynamic and photothermal therapy, is considered an emerging noninvasive strategy for cancer treatments. Organic molecules are promising theranostic agents because of their facile construction, simple modification, and good biocompatibility. Organic systems that integrated multifunctionalities in a single component and achieved high efficiency in both imaging and therapies are rarely reported as the inherently competitive energy relaxation pathways are hard to modulate, and fluorescence quenching occurs upon molecular aggregation. Herein, a versatile theranostic platform with near-infrared emission, high fluorescence quantum yield, robust reactive oxygen species production, and excellent photothermal conversion efficiency was developed based on an aggregation-induced emission luminogen, namely, TPA-TBT. In vivo studies revealed that the TPA-TBT nanoaggregates exhibit outstanding photodynamic and photothermal therapy efficacy to ablate tumors inoculated in a mouse model. This work offers a design strategy to develop one-for-all cancer theranostic agents by modulating and utilizing the relaxation energy of excitons in full.

H2 O2 -Responsive NIR-II AIE Nanobomb for Carbon Monoxide Boosting Low-Temperature Photothermal Therapy.

Low-temperature photothermal therapy (PTT), which circumvents the limitations of conventional PTT (e.g., thermotolerance and adverse effects), is an emerging therapeutic strategy which shows great potential for future clinical applications. The expression of heat shock proteins (HSPs) can dramatically impair the therapeutic efficacy of PTT. Thus, inhibition of HSPs repair and reducing the damage of nearby normal cells is crucial for improving the efficiency of low-temperature PTT. Herein, we developed a nanobomb based on the self-assembly of NIRII AIE polymer PBPTV and carbon monoxide (CO) carrier polymer mPEG(CO). This smart nanobomb can be exploded in a tumor microenvironment in which hydrogen peroxide is overexpressed and release CO into cancer cells to significantly inhibit the expression of HSPs and hence improve the antitumor efficiency of the low-temperature PTT.

Evoking Highly Immunogenic Ferroptosis Aided by Intramolecular Motion-Induced Photo-Hyperthermia for Cancer Therapy.

Immunogenic cell death (ICD) through apoptosis or necroptosis is widely adopted to improve the therapeutic effect in cancer treatment by triggering a specific antitumor immunity. However, the tumor resistance to apoptosis/necroptosis seriously impedes the therapeutic effect. Recently, ferroptosis featured with excessive lipid peroxidation is demonstrated capable of bypassing the apoptosis/necroptosis resistance to kill cancer cells. To date, numerous efficient ferroptosis inducers are developed and successfully utilized for sensitizing cancer cells to ferroptosis. Unfortunately, these inducers can hardly generate adequate immunogenicity during induction of ferroptotic cancer cell death, which distinctly attenuates the efficacy of triggering antitumor immune response, therefore leads to unsatisfactory therapeutic effect. Herein, a novel high-performance photothermal nanoparticle (TPA-NDTA NP) is designed by exploiting energy via excited-state intramolecular motion and employed for immensely assisting ferroptosis inducer to evoke highly efficient ICD through ferroptosis pathway. Tumor models with poor immunogenicity are used to demonstrate the tremendously enhanced therapeutic effect endowed by highly enhanced immunogenic ferroptosis in vitro and in vivo by virtue of the NPs. This study sheds new light on a previously unrecognized facet of boosting the immunogenicity of ferroptosis for achieving satisfactory therapeutic effect in cancer therapy.

Less is more: Silver-AIE core@shell nanoparticles for multimodality cancer imaging and synergistic therapy.

Nanomaterials with integrated multiple imaging and therapeutic modalities possess great potentials in accurate cancer diagnostics and enhanced therapeutic efficacy. Traditional strategies for achieving multimodality nanoplatform through one by one combination of different modalities are challenged by the complicated structural design and fabrication as well as inherent incompatibility between different modalities. Herein, a novel strategy is presented to realize multimodal imaging and synergistic therapy using a class of simple silver core/AIE (aggregation-induced emission) shell nanoparticles. In addition to the intrinsic AIE fluorescence (FL) and metal-based computed tomography (CT) and radiation therapy (RT) properties, an extra functionality at the core/shell interface was identified to enable excellent photothermal (PT) and photoacoustic (PA) performance. As a result, five imaging and therapy modalities (FL, CT, PA, photothermal therapy (PTT), and RT) were achieved with a single structural unit for sensitive tumor imaging and effective therapy.

Facile synthesis of AIEgens with wide color tunability for cellular imaging and therapy.

Luminogens with aggregation-induced emission (AIE) characteristics are nowadays undergoing explosive development in the fields of imaging, process visualization, diagnosis and therapy. However, exploration of an AIE luminogen (AIEgen) system allowing for extremely wide color tunability remains challenging. In this contribution, the facile synthesis of triphenylamine (TPA)-thiophene building block-based AIEgens having tunable maximum emission wavelengths covering violet, blue, green, yellow, orange, red, deep red and NIR regions is reported. The obtained AIEgens can be utilized as extraordinary fluorescent probes for lipid droplet (LD)-specific cell imaging and cell fusion assessment, showing excellent image contrast to the cell background and high photostability, as well as satisfactory visualization outcomes. Interestingly, quantitative evaluation of the phototherapy effect demonstrates that one of these presented AIEgens, namely TTNIR, performs well as a photosensitizer for photodynamic ablation of cancer cells upon white light irradiation. This study thus provides useful insights into rational design of fluorescence systems for widely tuning emission colors with high brightness, and remarkably extends the applications of AIEgens.

Boosting Non-Radiative Decay to Do Useful Work: Development of a Multi-Modality Theranostic System from an AIEgen.

The efficient utilization of energy dissipating from non-radiative excited-state decay of fluorophores was only rarely reported. Herein, we demonstrate how to boost the energy generation of non-radiative decay and use it for cancer theranostics. A novel compound (TFM) was synthesized which possesses a rotor-like twisted structure, strong absorption in the far red/near-infrared region, and it shows aggregation-induced emission (AIE). Molecular dynamics simulations reveal that the TFM aggregate is in an amorphous form consisting of disordered molecules in a loose packing state, which allows efficient intramolecular motions, and consequently elevates energy dissipation from the pathway of thermal deactivation. These intrinsic features enable TFM nanoparticles (NPs) to display a high photothermal conversion efficiency (51.2 %), an excellent photoacoustic (PA) effect, and effective reactive oxygen species (ROS) generation. In vivo evaluation shows that the TFM NPs are excellent candidates for PA imaging-guided phototherapy.

Exploration of biocompatible AIEgens from natural resources.

Luminogens with aggregation-induced emission (AIEgens) characteristics have been well developed and applied in various areas such as bio-imaging, theranostics, organic photoelectronics and chemo/bio sensors. However, most of the reported AIEgens suffer from the disadvantages of complex organic synthesis and high cost, as well as being environmentally unfriendly and hard to degrade, which have largely limited their real applications. In this work, we discovered berberine chloride, a natural isoquinoline alkaloid isolated from Chinese herbal plants, as an unconventional rotor-free AIEgen with bright solid-state emission and water-soluble characteristics. Single crystal structure analysis and optical property, viscosity, and host-guest interaction studies suggested that intramolecular vibration and twisted intramolecular charge transfer were responsible for the AIE phenomenon of berberine chloride. Moreover, berberine chloride was biocompatible and could specifically target lipid droplets in a fluorescence turn-on and wash-free manner, demonstrating the great potential of natural products as promising AIE probes.

A multifunctional luminogen with aggregation-induced emission characteristics for selective imaging and photodynamic killing of both cancer cells and Gram-positive bacteria.

The increasing impact of bacteria on cancer progression and treatments has been witnessed in recent years. Insufficient attention to cancer-related bacteria may lead to distant metastasis, poor therapeutic efficiency and low survival rates for cancers. Exploiting new approaches that enable selective imaging and effective killing of cancer cells and bacteria are thus of great value for the battle against cancers. Herein, we report an aggregation-induced emission (AIE) luminogen, namely TPPCN, with intense emission and efficient reactive oxygen species production for fluorescence imaging and killing cancer cells and Gram-positive bacteria. This work not only demonstrates the potential of AIE luminogens in comprehensive cancer treatments but also stimulates the enthusiasm of scientists to design more multifunctional AIE systems for both cancer and bacteria theranostics.

Highly Stable Organic Small Molecular Nanoparticles as an Advanced and Biocompatible Phototheranostic Agent of Tumor in Living Mice.

Near-infrared (NIR)-absorbing organic small molecules hold great promise as the phototheranostic agents for clinical translation by virtue of their intrinsic advantages such as well-defined chemical structure, high purity, and good reproducibility. However, most of the currently available ones face the challenges in varying degrees in terms of photothermal instability, and photobleaching/reactive oxygen nitrogen species (RONS) inresistance, which indeed impair their practical applications in precise diagnosis and treatment of diseases. Herein, we developed highly stable and biocompatible organic nanoparticles (ONPs) for effective phototheranostic application by design and synthesis of an organic small molecule (namely TPA-T-TQ) with intensive absorption in the NIR window. The TPA-T-TQ ONPs with no noticeable in vivo toxicity possess better capacities in photothermal conversion and photoacoustic imaging (PAI), as well as show far higher stabilities including thermal/photothermal stabilities, and photobleaching/RONS resistances, when compared with the clinically popularly used indocyanine green. Thanks to the combined merits, the ONPs can serve as an efficient probe for in vivo PAI in a high-contrast manner, which also significantly causes the stoppage of tumor growth in living mice through PAI-guided photothermal therapy. This study thus provides an insight into the development of advanced NIR-absorbing small molecules for practical phototheranostic applications.

Real-time monitoring of cell apoptosis and drug screening using fluorescent light-up probe with aggregation-induced emission characteristics.

Real-time monitoring of cell apoptosis could provide valuable insights into early detection of therapy efficiency and evaluation of disease progression. In this work, we designed and synthesized a new live-cell-permeable, fluorescent light-up probe for real-time cell apoptosis imaging. The probe is comprised of a hydrophilic caspase-specific Asp-Glu-Val-Asp (DEVD) peptide and a hydrophobic tetraphenylethene (TPE) unit, a typical fluorogen with aggregation-induced emission characteristics. In aqueous solution, the probe is almost nonfluorescent but displays significant fluorescence enhancement in response to caspase-3/-7, which are activated in the apoptotic process and able to cleave the DEVD moieties. This fluorescence "turn-on" response is ascribed to aggregation of cleaved hydrophobic TPE residues, which restricts the intramolecular rotations of TPE phenyl rings and populates the radiative decay channels. The light-up nature of the probe allows real-time monitoring of caspase-3/-7 activities both in solutions and in living cells with a high signal-to-noise ratio. The probe provides a new opportunity to screen enzyme inhibitors and evaluate the apoptosis-associated drug efficacy.