An Organophosphorescence Probe with Ultralong Lifetime and Intrinsic Tissue Selectivity for Specific Tumor Imaging and Guided Tumor Surgery.

Organic phosphorescent materials are excellent candidates for use in tumor imaging. However, a systematic comparison of the effects of the intensity, lifetime, and wavelength of phosphorescent emissions on bioimaging performance has not yet been undertaken. In addition, there have been few reports on organic phosphorescent materials that specifically distinguish tumors from normal tissues. This study addresses these gaps and reveals that longer lifetimes effectively increase the signal intensity, whereas longer wavelengths enhance the penetration depth. Conversely, a strong emission intensity with a short lifetime does not necessarily yield robust imaging signals. Building upon these findings, an organo-phosphorescent material with a lifetime of 0.94 s was designed for tumor imaging. Remarkably, the phosphorescent signals of various organic nanoparticles are nearly extinguished in blood-rich organs because of the quenching effect of iron ions. Moreover, for the first time, we demonstrated that iron ions universally quench the phosphorescence of organic room-temperature phosphorescent materials, which is an inherent property of such substances. Leveraging this property, both the normal liver and hepatitis tissues exhibit negligible phosphorescent signals, whereas liver tumors display intense phosphorescence. Therefore, phosphorescent materials, unlike chemiluminescent or fluorescent materials, can exploit this unique inherent property to selectively distinguish liver tumor tissues from normal tissues without additional modifications or treatments.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Enhancing NIR-II Imaging and Photothermal Therapy for Improved Oral Cancer Theranostics by Combining TICT and Aggregation-Induced Emission.

In the treatment process of cancers like oral cancer, it is necessary to employ extensive surgical resection to achieve cancer eradication. However, this often results in damage to crucial functions such as chewing and speaking, leading to a poorer prognosis and a reduced quality of life. To address this issue, a multifunctional theranostic agent named MBPN-T-BTD has been developed by precisely modulating the excitation state energy distribution in the radiative/nonradiative decay pathways using the characteristics of twisted intramolecular charge transfer and aggregation-induced emission. This agent outperforms clinically utilized indocyanine green (ICG) in various aspects, including the second near-infrared window (NIR-II, 1000-1700 nm) fluorescence (FL) and photothermal conversion efficiency (PCE). Its nanoparticle form (BTB NPs) can be effectively used for high-contrast delineation of lymph node mapping and tongue and floor of mouth cancers using NIR-II FL, enabling surgeons to achieve more precise and thorough tumor clearance. For tumors located in close proximity to vital organs such as the tongue, the exceptional PCE (71.96%) of BTB NPs allows for targeted photothermal ablation with minimal damage to peripheral healthy tissues. This contribution provides a safer and more effective paradigm for minimally invasive or noninvasive treatment of oral cancer, ensuring the preservation of normal organ functions and showing potential for improving the overall prognosis and quality of life for cancer patients.

Observing Extracellular Vesicles Originating from Endothelial Cells in Vivo Demonstrates Improved Astrocyte Function Following Ischemic Stroke via Aggregation-Induced Emission Luminogens.

Extracellular vesicles (EVs) obtained from endothelial cells (ECs) have significant therapeutic potential in the clinical management of individuals with ischemic stroke (IS) because they effectively treat ischemic stroke in animal models. However, because molecular probes with both high labeling efficiency and tracer stability are lacking, monitoring the actions of EC-EVs in the brain remains difficult. The specific intracellular targets in the brain that EC-EVs act on to produce their protective effects are still unknown, greatly impeding their use in clinical settings. For this research, we created a probe that possessed aggregation-induced emission (AIE) traits (namely, TTCP), enabling the effective labeling of EC-EVs while preserving their physiological properties. In vitro, TTCP simultaneously had a higher EC-EV labeling efficiency and better tracer stability than the commercial EV tags PKH-67 and DiI. In vivo, TTCP precisely tracked the actions of EC-EVs in a mouse IS model without influencing their protective effects. Furthermore, through the utilization of TTCP, it was determined that astrocytes were the specific cells affected by EC-EVs and that EC-EVs exhibited a safeguarding impact on astrocytes following cerebral ischemia-reperfusion (I/R) injury. These protective effects encompassed the reduction of the inflammatory reaction and apoptosis as well as the enhancement of cell proliferation. Further analysis showed that miRNA-155-5p carried by EC-EVs is responsible for these protective effects via regulation of the c-Fos/AP-1 pathway; this information provided a strategy for IS therapy. In conclusion, TTCP has a high EC-EV labeling efficiency and favorable in vivo tracer stability during IS therapy. Moreover, EC-EVs are absorbed by astrocytes during cerebral I/R injury and promote the restoration of neurological function through the regulation of the c-Fos/AP-1 signaling pathway.

ROS Responsive Nanoparticles Encapsulated with Natural Medicine Remodel Autophagy Homeostasis in Breast Cancer.

In photodynamic therapy (PDT), elevated reactive oxygen species (ROS) activate tumor cell protective autophagy, therefore attenuating the antitumor function of therapy. Hence, inhibition of protective autophagy in tumors can improve the antitumor effect of PDT. Herein, an innovative nanotraditional Chinese medicine system ((TP+A)@TkPEG NPs), which remodeled autophagy homeostasis, was fabricated. A photosensitizer aggregation inducing emission (AIE) and autophagy modulator triptolide (TP, an active ingredient of Tripterygium wilfordii Hook F) were encapsulated into ROS-responsive nanoparticles to improve antitumor effect of PDT in treatment of triple negative breast cancer. We proved that (TP+A)@TkPEG NPs effectively elevated intracellular ROS levels, activated ROS-responsive release of TP and inhibited the proliferation of 4T1 cells in vitro. More importantly, it sharply reduced autophagy related genes transcription and proteins expression in 4T1 cells, then promote cell apoptosis. In addition, this nanoherb therapeutic system effectively orientated to tumor sites, achieved efficient inhibition of tumor, and extended the survival time of 4T1-bearing mice in vivo. Further results confirmed that (TP+A)@TkPEG NPs remarkably inhibit the expression level of autophagy related initiation gene (becline-1) and elongation protein (light chain 3B) in tumor microenvironment and then block PDT induced protective autophagy. In brief, this system can remodel autophagy homeostasis and serve as an innovative approach for treatment of triple negative breast cancer.

Smart One-for-All Agent with Adaptive Functions for Improving Photoacoustic /Fluorescence Imaging-Guided Photodynamic Immunotherapy.

Multifunctional phototheranostics that integrate several diagnostic and therapeutic strategies into one platform hold great promise for precision medicine. However, it is really difficult for one molecule to possess multimodality optical imaging and therapy properties that all functions are in the optimized mode because the absorbed photoenergy is fixed. Herein, a smart one-for-all nanoagent that the photophysical energy transformation processes can be facilely tuned by external light stimuli is developed for precise multifunctional image-guided therapy. A dithienylethene-based molecule is designed and synthesized because it has two light-switchable forms. In the ring-closed form, most of the absorbed energy dissipates via nonradiative thermal deactivation for photoacoustic (PA) imaging. In the ring-open form, the molecule possesses obvious aggregation-induced emission features with excellent fluorescence and photodynamic therapy properties. In vivo experiments demonstrate that preoperative PA and fluorescence imaging help to delineate tumors in a high-contrast manner, and intraoperative fluorescence imaging is able to sensitively detect tiny residual tumors. Furthermore, the nanoagent can induce immunogenic cell death to elicit antitumor immunity and significantly suppress solid tumors. This work develops a smart one-for-all agent that the photophysical energy transformation and related phototheranostic properties can be optimized by light-driven structure switch, which is promising for multifunctional biomedical applications.

An AIEgen-based "turn-on" probe for sensing cancer cells and tiny tumors with high furin expression.

Peptide-aggregation-induced emission (AIE) luminogen (AIEgen) conjugates are widely used in the bioimaging field for their good resistance to photobleaching, red and near-infrared light emission, good biocompatibility, etc. However, their peptides are mainly negatively charged and the positively charged peptide-AIEgen conjugates are rarely used in in vivo imaging due to their high non-specific interaction with protein to cause "false-positive" results and their potential risk of triggering hemolysis. Herein, we introduce a black hole quencher 3 (BHQ3) to RVRRGFF-AIE (FA) to build a "turn-on" probe, named BHQ3-RVRRGFF-AIE (BFA). Compared with FA, BFA has advantages in the anti-interference ability for different proteins and many solution environments. But, both BFA and FA have high risks of inducing hemolysis, which restricts their further application. Through co-assembly with poly-γ-glutamic acid (γ-PGA), molecular probes BFA and FA are formed into PGA-BFA and PGA-FA nanoparticles with high biocompatibility and suppressed phototoxicity. Cell studies show that PGA-BFA can discriminate cancer cells with high furin expression from low furin-expressed cancer cells and normal cells. In vivo studies show that PGA-BFA can light up tiny tumors in the abdominal cavity with a better tumor-to-intestine ratio (3.14) than that of PGA-FA (1.47), which is helpful for the accurate excision of tiny tumors. This study will advance the development of constructing good biosafety probes with a high signal-to-noise ratio for fluorescence image-guided cancer surgery.

Phototheranostic nanoparticles with aggregation-induced emission as a four-modal imaging platform for image-guided photothermal therapy and ferroptosis of tumor cells.

Due to the aggregation-caused quenching (ACQ) and weak photo-penetrating ability, the application of phototheranostic agents in drug delivery field is greatly limited. Ferroptosis, a newly discovered cell death mode, has not been extensively studied in the field of phototherapy up to now. Here, a new near-infrared II (NIR-II) molecule with aggregation-induced emission (AIE) property (named TSST) co-assembled with DHA-PEG and ferrocene as nanoparticles (DFT-NP), which was rationally designed and synthesized. The DFT-NP exhibited enhanced NIR-II fluorescence, photothermal, photoacoustic, magnetic resonance imaging, AIE and ferroptosis capacities. The NIR-II fluorescence intensity of obtained nanoparticles was improved, owing to the strong interaction between DHA and TSST, which limited the intramolecular rotation restriction and non-radiative attenuation of TSST to discourage energy dissipation in aggregation state. Inspiringly, the generated photothermal effect by DFT-NP can promote the Fenton reaction of ferrocene and H2O2, resulting in dissolution of the nanoparticles and cancer cells expedited ferroptosis via accumulation lipid free radicals of DHA. The released TSST enhanced the photothermal and photoacoustic imaging effects through removing the DHA restriction to restore the non-radiative attenuation. This work is the first example of nanoparticles that integrates four-mode imaging, photothermal and ferroptosis-induced therapy functions, which offers great advantages for potential clinical applications.

Biosynthetic Dendritic Cell-Exocytosed Aggregation-Induced Emission Nanoparticles for Synergistic Photodynamic Immunotherapy.

Dendritic cell (DC)-derived small extracellular vesicles (DEVs) are recognized as a highly promising alternative to DC vaccines; however, the clinical testing of DEV-based immunotherapy has shown limited therapeutic efficacy. Herein, we develop a straightforward strategy in which DCs serve as a cell reactor to exocytose high-efficient DEV-mimicking aggregation-induced emission (AIE) nanoparticles (DEV-AIE NPs) at a scaled-up yield for synergistic photodynamic immunotherapy. Exocytosed DEV-AIE NPs inherit not only the immune-modulation proteins from parental DCs, enabling T cell activation, but also the loaded AIE-photosensitizer MBPN-TCyP, inducing superior immunogenic cell death (ICD) by selectively accumulating in the mitochondria of tumor cells. Eventually, DEV-AIE synergistic photodynamic immunotherapy elicits dramatic immune responses and efficient eradication of primary tumors, distant tumors, and tumor metastases. In addition, cancer stem cells (CSCs) in 4T1 and CT26 solid tumors were significantly inhibited by the immune functional DEV-AIE NPs. Our work presents a facile method for the cellular generation of EV-biomimetic NPs and demonstrates that the integration of DEVs and AIE photosensitizers is a powerful direction for the production of clinical anticancer nanovaccines.

Ultrasonic-assisted extraction of polyphenolic compounds from Paederia scandens (Lour.) Merr. Using deep eutectic solvent: optimization, identification, and comparison with traditional methods.

Ultrasonic-assisted extraction (UAE) coupled with deep eutectic solvent (DES) is a novel, efficient and green extraction method for phytochemicals. In this study, the effects of 16 DESs coupled with UAE on the extraction rate of polyphenols from Paederia scandens (Lour.) Merr. (P. scandens), an edible and medicinal herb, were investigated. DES synthesised with choline chloride and ethylene glycol at a 1:2 M ratio resulted in the highest extractability. Moreover, the effects of extraction parameters were investigated by using a two-level factorial experiment followed by response surface methodology The optimal parameters (water content in DES of 49.2%, the actual ultrasonic power of 72.4 W, and ultrasonic time of 9.7 min) resulted in the optimal total flavonoid content (TFC) (27.04 mg CE/g DW), ferric-reducing antioxidant power (FRAP) value (373.27 µmol Fe(Ⅱ)E/g DW) and 2,2'-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid radical (ABTS+) value (48.64 µmol TE/g DW), closely matching the experimental results. Furthermore, a comparison study demonstrated that DES-UAE afforded the higher TFC and FRAP value than traditional extraction methods. 36 individual polyphenolic compounds were identified and quantified by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) in P. scandens extracts, and of which 30 were found in the extracts obtained by DES-UAE. Additionally, DES-UAE afforded the highest sum of individual polyphenolic compound content. These results revealed that DES-UAE enhanced the extraction efficiency for polyphenols and provided a scientific basis for further processing and utilization of P. scandens.

Species-specific bioaccumulation and health risk assessment of heavy metal in seaweeds in tropic coasts of South China Sea.

Seaweeds are widely known superfood in coasts where most anthropogenic heavy metal discharges are inputted and stored. The present study analyzed 11 seaweed species and 13 heavy metals to test the hypothesis that the species-specific capacity of heavy metal bioaccumulation had great significance to health risk of human. The seaweeds were collected from tropic coasts of Hainan Island. We comparatively determined the bioaccumulation level of metals in different species. The results revealed that the red algae mainly concentrated V, Se, Mn, Ni, and Ag. The brown algae mainly concentrated Cr, Co, Cu, Cd, As and Fe, while the green algae mainly concentrated Zn and Pb. The cluster analysis, principal component analysis and metal pollution index indicated that Padina crassa, Sargassum thunbergii, Caulerpa racemosa and Asparagopsis taxiformis showed similar metal bioaccumulation behavior. The health risk assessment revealed that the overall hazard index (HI) of seaweeds consumption to adults was less than 1, while the HI of Sargassum oligocystum, Turbinaria ornate, Sargassum polycystum and Sargassum thunbergii consumption to children was greater than 1, suggesting a moderate or high risk to children. Moreover, the exposure amount and the carcinogenic risk parameter indicated that As and Cr were the limiting factor for seaweeds consumption. Overall, our findings here largely supported our hypothesis that the heavy metal bioaccumulation behavior and health risk was highly variable and complex among different species. We thus suggested that the species-specific health risk of heavy metals in seaweeds should be cautiously evaluated in natural environments.

Effects of different extraction methods on contents, profiles, and antioxidant abilities of free and bound phenolics of Sargassum polycystum from the South China Sea.

Total phenolic content (TPC), phenolic profiles, and antioxidant activity of free and bound extracts of Sargassum polycystum, obtained by different extraction solvents and hydrolysis methods, were investigated. Aqueous acetone afforded the highest free TPC and antioxidant ability, followed by aqueous ethanol and aqueous methanol. Twelve free phenolic compounds were identified by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS), including two hydroxycinnamic acids, seven flavonoids, one stilbene, and two phlorotannins. Three to nine different free phenolic compounds were extracted by these solvents with different compositions, including nine by 70% acetone and eight by 70% methanol, 70% ethanol, and 50% ethanol. The highest total content of free phenolic compounds determined by high-performance liquid chromatography-diode array detection was obtained from 70% ethanol. Alkaline hydrolysis afforded higher bound TPC (274.27 mg GAE/100 g DW) and antioxidant ability than acid hydrolysis. Five bound phenolic compounds were characterized by UHPLC-MS and five were released from alkaline hydrolysis, whereas two were released from acid hydrolysis. Total content of bound phenolic compounds released by alkaline hydrolysis was 14.68-fold higher than that by acid hydrolysis. The free and bound TPC, phenolic profiles, and antioxidant activities depended on the extraction solvent used. These results indicate that S. polycystum is a potentially useful antioxidant source and contribute to the development of seaweed-based functional foods. PRACTICAL APPLICATION: Phenolics are usually divided into free and bound forms based on their extractability and interaction with cell wall components. The nutritional effects of bound phenolics in algae have long been neglected. These topics contribute to the development of seaweed-based functional foods.

Guest-host doped strategy for constructing ultralong-lifetime near-infrared organic phosphorescence materials for bioimaging.

Organic near-infrared room temperature phosphorescence materials have unparalleled advantages in bioimaging due to their excellent penetrability. However, limited by the energy gap law, the near-infrared phosphorescence materials (>650 nm) are very rare, moreover, the phosphorescence lifetimes of these materials are very short. In this work, we have obtained organic room temperature phosphorescence materials with long wavelengths (600/657-681/732 nm) and long lifetimes (102-324 ms) for the first time through the guest-host doped strategy. The guest molecule has sufficient conjugation to reduce the lowest triplet energy level and the host assists the guest in exciton transfer and inhibits the non-radiative transition of guest excitons. These materials exhibit good tissue penetration in bioimaging. Thanks to the characteristic of long lifetime and long wavelength emissive phosphorescence materials, the tumor imaging in living mice with a signal to background ratio value as high as 43 is successfully realized. This work provides a practical solution for the construction of organic phosphorescence materials with both long wavelengths and long lifetimes.

Amplification of Activated Near-Infrared Afterglow Luminescence by Introducing Twisted Molecular Geometry for Understanding Neutrophil-Involved Diseases.

Understanding the mechanism and progression of neutrophil-involved diseases (e.g., acute inflammation) is of great importance. However, current available analytical methods neither achieve the real-time monitoring nor provide dynamic information during the pathological processes. Herein, a peroxynitrite (ONOO-) and environmental pH dual-responsive afterglow luminescent nanoprobe is designed and synthesized. In the presence of ONOO- at physiological pH, the nanoprobes show activated near-infrared afterglow luminescence, whose intensity and lasting time can be highly enhanced by introducing the aggregation-induced emission (AIE) effect with a twisted molecular geometry into the system. In vivo studies using three diseased animal models demonstrate that the nanoprobes can sensitively reveal the development process of acute skin inflammation including infiltration of first arrived neutrophils and acidification initiating time, make a fast and accurate discrimination between allergy and inflammation, and rapidly screen the antitumor drugs capable of inducing immunogenic cell death. This work provides an alternative approach and advanced probes permitting precise disease monitoring in real time.

Boosting Photothermal Theranostics via TICT and Molecular Motions for Photohyperthermia Therapy of Muscle-Invasive Bladder Cancer.

The development of photothermal agents with high photothermal conversion efficiency (PCE) can help to reduce drug and laser dosage, but still remains a big challenge. Herein, a novel approach is reported to design photothermal agents with high PCE values by promoting nonradiative heat generation processes through the cooperation of twisted intramolecular charge transfer (TICT) and molecular motions. Within the designed molecule 2DMTT-BBTD, the tetraphenylethenes act as molecular rotors, the long alkyl chain grafted thiophene helps to twist the molecular geometry to facilitate TICT state formation and preserve molecular motions in aggregate, while the strong electron-withdrawing BBTD unit enhances TICT effect. 2DMTT-BBTD exhibits NIR-absorption and a high PCE value of 74.8% under 808 nm laser irradiation. Gambogic acid (GA) which surmounts tumor cell thermotolerance by inhibiting heat shock protein 90 (HSP90) expression is coloaded into the nanoparticles, RGD peptide is further introduced to the nanoparticle surface to improve tumor accumulation. The resultant nanoparticles facilitate the effective low-temperature hyperthermia therapy of muscle-invasive bladder cancer (MIBC) with minimal damage to surrounding heathy tissues. This work delivers a new design concept for development of highly efficient photothermal agents, which also provides a safer approach for noninvasive treatment of MIBC and other malignant tumors.

Boosting Photoacoustic Effect via Intramolecular Motions Amplifying Thermal-to-Acoustic Conversion Efficiency for Adaptive Image-Guided Cancer Surgery.

Photoacoustic (PA) imaging emerges as a promising technique for biomedical applications. The development of new strategies to boost PA conversion without depressing other properties (e.g., fluorescence) is highly desirable for multifunctional imaging but difficult to realize. Here, we report a new phenomenon that active intramolecular motions could promote PA signal by specifically increasing thermal-to-acoustic conversion efficiency. The compound with intense intramolecular motion exhibits amplified PA signal by elevating thermal-to-acoustic conversion, and the fluorescence also increases due to aggregation-induced emission signature. The simultaneously high PA and fluorescence brightness of TPA-TQ3 NPs enable precise image-guided surgery. The preoperative fluorescence and PA imaging are capable of locating orthotopic breast tumor in a high-contrast manner, and the intraoperative fluorescence imaging delineates tiny residual tumors. This study highlights a new design guideline of intramolecular motion amplifying PA effect.

High Performance of Simple Organic Phosphorescence Host-Guest Materials and their Application in Time-Resolved Bioimaging.

The study of purely organic room-temperature phosphorescence (RTP) has drawn increasing attention because of its considerable theoretical research and practical application value. Currently, organic RTP materials with both high efficiency (ΦP  > 20%) and a long lifetime (τP  > 10 s) in air are still scarce due to the lack of related design guidance. Here, a new strategy to increase the phosphorescence performance of organic materials by integrating the RTP host and RTP guest in one doping system to form a triplet exciplex, is reported. With these materials, the high-contrast labeling of tumors in living mice and encrypted patterns in thermal printing are both successfully realized by taking advantage of both the long afterglow time (up to 25 min in aqueous media) and high phosphorescence efficiency (43%).

Boosting Room Temperature Phosphorescence Performance by Alkyl Modification for Intravital Orthotopic Lung Tumor Imaging.

Pure organic persistent room temperature phosphorescence (RTP) materials have attracted wide attention owing to their great potential in various applications, particularly in bioimaging. However, it is still a challenge to manufacture organic RTP materials possessing quite high efficiency and long lifetime, owing to the high requirements for triplet excitons. In this study, a series of keto derivatives with efficient RTP in crystals are developed through the regulation of molecular aggregation states by simple alkyl groups, resulting in impressive luminescence performance with a longer lifetime and higher efficiency of up to 868 ms and 51.59%, respectively. All the alkyl-substituted derivatives exhibit bright RTP intensities after heavy grinding with a pestle, indicating their robust RTP features, which are suitable for many fields. Encouraged by the excellent RTP performance of these luminogens in the crystalline state, successful orthotopic lung tumor imaging with a high signal-to-background ratio (SBR) of 65 is demonstrated in this study to provide the promise of pure organic RTP materials for disease diagnosis, which hold the advantages of low autofluorescence interference and high signal-to-background ratio.

Supramolecular Aggregation-Induced Emission Nanodots with Programmed Tumor Microenvironment Responsiveness for Image-Guided Orthotopic Pancreatic Cancer Therapy.

Supramolecular nanomaterials as drug carriers have recently received increasing attention due to their intrinsic merits such as high stability, strong inclusion capability, and facile modification of the parental structure; however, intelligent ones with combined capacities of long blood circulation, highly efficient tumor cell uptake, and site-oriented drug release inside tumor cells are still rather limited. Herein, we report a strategy using supramolecular aggregation-induced emission (AIE) nanodots for image-guided drug delivery, which integrate both the advantages of AIE and supramolecular nanomaterials. The supramolecular AIE dots are prepared by the host-guest coassembly of the matrix metalloproteinase-2 (MMP-2) sensitive PEG-peptide (PEG2000-RRRRRRRR (R8)-PLGLAG-EKEKEKEKEKEK (EK6)) and functional α-cyclodextrins (α-CD) derivatives that are conjugated with the anticancer drug gemcitabine (GEM) and a far-red/near-infrared fluorescent rhodanine-3-acetic acid-based AIE luminogen, respectively. The supramolecular AIE dots realize long blood circulation time by virtue of the zwitterionic stealth peptide EK6. After largely accumulating in tumor tissues by the enhanced permeability and retention effect, the supramolecular AIE dots can successively respond to the tumor-overexpressed MMP-2 and intracellular reductive microenvironment, achieving both enhanced cancer cellular uptake and selective GEM release within cancer cells, which thus exhibit excellent tumor inhibition ability in both subcutaneous and orthotopic pancreatic tumor models.

AIEgens Conjugation Improves the Photothermal Efficacy and Near-Infrared Imaging of Heptamethine Cyanine IR-780.

Near-infrared (NIR) fluorescent probes can deeply penetrate through tissues with little damage. To facilitate image-guided theranostics, researchers usually apply a desired amount of photosensitizers to achieve effective photothermal responses. However, these probes could easily suffer from low photostability and aggregated-caused quenching effect in high concentrations. In this paper, the rational incorporation of an aggregated-induced emission (AIE) unit into the structure of heptamethine cyanine IR-780 is reported. Using tetraphenylethene (TPE) as an AIE core, we synthesize three TPE-modified IR-780 probes (IR-780 AIEgens) via different linkages. The IR-780 derivatives all show enhanced AIE features, in which the probe with an ether linkage (IR780-O-TPE) is superior in rapid cell uptake, high targeting capacity, and good photostability. Moreover, IR780-O-TPE exhibits the strongest cytotoxicity to HeLa cells (IC50 = 3.3 µM). The three IR-780 derivatives displayed a photothermal response in a concentration-dependent manner, in which IR-780 AIEgens are more cytotoxic than IR-780, with IC50 of 0.3 µM under 808 nm laser irradiation. In tumor-bearing mice, the optimal probe IR780-O-TPE also showed a more effective photothermal response than IR-780. By illustrating the relationship between aggregation state with photophysical properties, cell imaging, and cytotoxicity, this work is helpful in modulating NIR-based photosensitizers into AIE features for efficient image-guided theranostics.