Promoted NIR-II Fluorescence by Heteroatom-Inserted Rigid-Planar Cores for Monitoring Cell Therapy of Acute Lung Injury.

Fluorophores with emission in the second near-infrared (NIR-II) window have displayed salient advantages for biomedical applications. However, exploration of new luminogens with high NIR-II fluorescent brightness is still challenging. Herein, based on the "ring-fusion" strategy, a series of heteroatom-inserted rigid-planar cores is proposed to achieve the bathochromic NIR-II fluorophores with aggregation-induced emission (AIE) performance. Interestingly, one of the representative fluorophores, 4,4'-(5,5'-([1,2,5]thiadiazolo[3,4-i]dithieno[2,3-a:3',2'-c]phenazine-8,12-diyl)bis(4-octylthiophene-5,2-diyl))bis(N,N-diphenylaniline) (TTQiT), enjoys a maximum emission beyond 1100 nm because of the efficiently narrowed energy bandgap by electron-rich sulfur-atom-inserted core, which is verified by theoretical calculation. Taking advantage of the bright NIR-II emission of TTQiT nanoparticles, the desirable in vivo NIR-II imaging with high signal-to-background ratios is successfully performed and a long-term stem cell tracking in the detection of acute lung injury is further realized. Therefore, it is anticipated that this work will provide a promising molecular engineering strategy to enrich the scope of NIR-II fluorophores for catering to diverse demands in biomedical applications.

A Multispectral Photoacoustic Tracking Strategy for Wide-Field and Real-Time Monitoring of Macrophages in Inflammation.

Inflammation is a common defensive response of the vascular system that involves the activation and mediation of immune cell and stem cell homing. However, it is usually hard to track and analyze the real-time status of these cell types toward the inflammation microenvironment in a large field of view with desired resolution. Here, we designed and synthesized near-infrared absorbing semiconducting polymer nanoparticles, BBT-TQP-NP (BTNPs), as the cell tracker and utilized their photoacoustic activity to unveil the targeting behaviors of macrophages, neutrophils, and mesenchymal stem cells to the inflamed sites in mice. Facilitated by multispectral optical-resolution photoacoustic microscopy (ORPAM), we can continuously monitor the in vivo photoacoustic signals of the labeled cells with cellular resolution in a wide-field (a circle field-of-view with a diameter of 9 mm). In addition, the highly sensitive observation of vascular microstructures and labeled cells can reveal the time-dependent accumulating behaviors of various cell types toward inflammation sites. As a result, our study offers an effective and promising tracking strategy to analyze the in vivo status and fate of functional cells in targeting the diseased/damaged regions.

NIR-II Absorbing Semiconducting Polymer-Triggered Gene-Directed Enzyme Prodrug Therapy for Cancer Treatment.

Exploration of facile strategies for precise regulation of target gene expression remains highly challenging in the development of gene therapies. Especially, a stimuli-responsive nanocarrier integrated with ability of noninvasive remote control for treating wide types of cancers is rarely developed. Herein, a NIR-II absorbing semiconducting polymer (PBDTQ) is employed to remotely activate the heat-inducible heat-shock protein 70 (HSP70) promoter under laser irradiation, further realizing regulation of gene-directed enzyme prodrug therapy (GDEPT) for cancer treatment in mild hyperthermia. In this multifunctional nanocomposite, the PBDTQ and double suicide gene plasmid (pSG) based on HSP70 promoter are incorporated into a lipid complex. Upon NIR-II laser excitation, the mild photothermal effect (≈43 °C) generated from PBDTQ can cause the release of pSG and activation of HSP70 promoter, and then upregulate suicide gene expression triggered by the HSP70 promoter which can further convert the nontoxic prodrug into its cytotoxic metabolites. Therefore, this work demonstrates a universal NIR-II laser-triggered GDEPT using semiconducting polymers as the photothermal generator for cancer treatment with minimized collateral damage and nontargeted side effects.

Stable Perovskite Solar Cells Using Molecularly Engineered Functionalized Oligothiophenes as Low-Cost Hole-Transporting Materials.

Triarylamine-substituted bithiophene (BT-4D), terthiophene (TT-4D), and quarterthiophene (QT-4D) small molecules are synthesized and used as low-cost hole-transporting materials (HTMs) for perovskite solar cells (PSCs). The optoelectronic, electrochemical, and thermal properties of the compounds are investigated systematically. The BT-4D, TT-4D, and QT-4D compounds exhibit thermal decomposition temperature over 400 °C. The n-i-p configured perovskite solar cells (PSCs) fabricated with BT-4D as HTM show the maximum power conversion efficiency (PCE) of 19.34% owing to its better hole-extracting properties and film formation compared to TT-4D and QT-4D, which exhibit PCE of 17% and 16%, respectively. Importantly, PSCs using BT-4D demonstrate exceptional stability by retaining 98% of its initial PCE after 1186 h of continuous 1 sun illumination. The remarkable long-term stability and facile synthetic procedure of BT-4D show a great promise for efficient, stable, and low-cost HTMs for PSCs for commercial applications.

NIR-II Fluorescent Brightness Promoted by "Ring Fusion" for the Detection of Intestinal Inflammation.

Fluorophores with emission in the second near-infrared window (NIR-II) have displayed salient advantages for biomedical applications. However, the common strategy of reducing the energy bandgap of fluorophores so as to achieve red-shifted wavelengths always leads to compromised fluorescent brightness. Herein, we propose a molecular design concept of "ring-fusion" to modify the acceptor of AIEgen that can extend the luminous wavelength from NIR-I to NIR-II. The fused-acceptor-containing fluorophore yielded, TTQP, has an enhanced absorption coefficient with a higher brightness in nanoparticle formation compared to its NIR-I emissive counterpart (TTQ-DP) with a non-fused acceptor. Theoretical calculation further confirms that the ring fusion can efficiently promote the rigidity and planarity of the electron-deficient core, leading to a lower reorganization energy and nonradiative decay. The TTQP NPs yielded thus allow sensitive NIR-II fluorescence imaging of vasculature and intestinal inflammation in mice models. Therefore, we anticipate that our work will provide a promising molecular-engineering strategy to enrich the library and broaden the application scope of NIR-II fluorophores.

Acceptor Engineering for Optimized ROS Generation Facilitates Reprogramming Macrophages to M1 Phenotype in Photodynamic Immunotherapy.

Reprogramming tumor-associated macrophages to an antitumor M1 phenotype by photodynamic therapy is a promising strategy to overcome the immunosuppression of tumor microenvironment for boosted immunotherapy. However, it remains unclear how the reactive oxygen species (ROS) generated from type I and II mechanisms, relate to the macrophage polarization efficacy. Herein, we design and synthesize three donor-acceptor structured photosensitizers with varied ROS-generating efficiencies. Surprisingly, we discovered that the extracellular ROS generated from type I mechanism are mainly responsible for reprogramming the macrophages from a pro-tumor type (M2) to an anti-tumor state (M1). In vivo experiments prove that the photosensitizer can trigger photodynamic immunotherapy for effective suppression of the tumor growth, while the therapeutic outcome is abolished with depleted macrophages. Overall, our strategy highlights the designing guideline of macrophage-activatable photosensitizers.

Planar AIEgens with Enhanced Solid-State Luminescence and ROS Generation for Multidrug-Resistant Bacteria Treatment.

Planar luminogens have encountered difficulties in overcoming intrinsic aggregation-caused emission quenching by intermolecular π-π stacking interactions. Although excited-state double-bond reorganization (ESDBR) can guide us on designing planar aggregation-induced emission (AIE) luminogens (AIEgens), its mechanism has yet been elucidated. Major challenges in the field include methods to efficiently restrict ESDBR and enhance AIE performance without using bulky substituents (e.g., tetraphenylethylene and triphenylamine). In this study, we rationally developed fluoro-substituent AIEgens with stronger intermolecular H-bonding interaction for restricted molecular motions and increased crystal density, leading to decreased nonradiative decay rate by one order of magnitude. The adjusted ESDBR properties also show a corresponding response to variation in viscosity. Furthermore, their aggregation-induced reactive oxygen species (ROS) generations have been discovered. The application of such planar AIEgen in treating multidrug-resistant bacteria has been demonstrated in a mouse model. The relationship between ROS generation and distinct E/Z-configurational stacking behaviors have been further understood, providing a design principle for synthesizing planar AIEgen-based photosensitizers.

A Photoinduced Nonadiabatic Decay-Guided Molecular Motor Triggers Effective Photothermal Conversion for Cancer Therapy.

It remains highly challenging to identify small molecule-based photothermal agents with a high photothermal conversion efficiency (PTCE). Herein, we adopt a double bond-based molecular motor concept to develop a new class of small photothermal agents to break the current design bottleneck. As the double-bond is twisted by strong twisted intramolecular charge transfer (TICT) upon irradiation, the excited agents can deactivate non-radiatively through the conical intersection (CI) of internal conversion, which is called photoinduced nonadiabatic decay. Such agents possess a high PTCE of 90.0 %, facilitating low-temperature photothermal therapy in the presence of a heat shock protein 70 inhibitor. In addition, the behavior and mechanism of NIR laser-triggered molecular motions for generating heat through the CI pathway have been further understood through theoretical and experimental evidence, providing a design principle for highly efficient photothermal and photoacoustic agents.

Sub-10†nm Aggregation-Induced Emission Quantum Dots Assembled by Microfluidics for Enhanced Tumor Targeting and Reduced Retention in the Liver.

A robust platform is developed to assemble sub-10 nm organic aggregation-induced emission (AIE) particles using four different AIE luminogens (AIEgens) with emissions from green to the second near-infrared window (NIR-II). They are called AIE quantum dots (QDs) to distinguish from typical AIE dots which are larger than 25 nm. Compared with AIE dots that are larger than 25 nm, AIE QDs allow more efficient cellular uptake and imaging without surface modification of any membrane-penetrating peptides or other targeting molecules. NIR-II AIEgens, which have nearly no background fluorescence from organisms, are used to demonstrate that AIE QDs can achieve high contrast at the tumor as small as 80 mm3 and evade the liver more efficiently than AIE dots. AIE QDs hold a good promise for sensitive and precise diagnosis of the latent solid tumor in clinical medicine with much lower off-targeting to the liver than AIE dots.

An Ester-Substituted Semiconducting Polymer with Efficient Nonradiative Decay Enhances NIR-II Photoacoustic Performance for Monitoring of Tumor Growth.

Photoacoustic agents have been of vital importance for improving the imaging contrast and reliability against self-interference from endogenous substances. Herein, we synthesized a series of thiadiazoloquinoxaline (TQ)-based semiconducting polymers (SPs) with a broad absorption covering from NIR-I to NIR-II regions. Among them, the excited s-BDT-TQE, a repeating unit of SPs, shows a large dihedral angle and narrow adiabatic energy as well as low radiative decay, attributing to its strongly electron-deficient ester-substituted TQ-segment. In addition, its more vigorous molecular motions trigger a higher reorganization energy that further yields an efficient photoinduced nonradiative decay, which has been carefully examined and understood by theoretical calculation. Thus, BDT-TQE SP-cored nanoparticles with twisted intramolecular charge transfer (TICT) feature exhibit a high NIR-II photothermal conversion efficiency (61.6 %) and preferable PA tracking of in situ hepatic tumor growth for more than 20 days. This study highlights a unique strategy for constructing efficient NIR-II photoacoustic agents via TICT-enhanced PNRD effect, advancing their applications for in vivo bioimaging.

SwissKnife-Inspired Multifunctional Fluorescence Probes for Cellular Organelle Targeting Based on Simple AIEgens.

Facile, efficient, and mass production of aggregation-induced emission (AIE) luminogens (AIEgens) with excited-state intramolecular proton transfer (ESIPT) characteristics was achieved by a one-step condensation reaction of 2-(hydrazonomethyl)phenol with benzaldehydes. The function of as-prepared AIEgens could be tuned easily by varying the functional group being carried on the phenyl ring of benzaldehyde just like a Swiss knife handle. The suitable distance and angle of the intramolecular hydrogen bond in these AIEgens endowed them with ESIPT properties, intense solid-state luminescence, and large Stokes shifts (155-169 nm). These AIEgens could not only serve as biological probes showing specific targeting to lipid droplets, endoplasmic reticulum, and lysosomes, respectively, but also generate reactive oxygen species upon visible light irradiation to make them promise for photodynamic therapy.

Bicyclopentadithiophene-Based Organic Semiconductor for Stable and High-Performance Perovskite Solar Cells Exceeding 22.

Well-performing organic-inorganic halide perovskites are susceptible to poor efficiency and instability due to their various defects at the interphases, grain boundaries (GBs), and surfaces. In this study, an in situ method is utilized for effectively passivating the under-coordinated Pb2+ defects of perovskite with new non-fullerene acceptors (NFAs) (INXBCDT; X = H, Cl, and Br) through their carbonyl and cyano functional groups during the antisolvent dripping process. It reveals that the bicyclopentadithiophene (BCDT) core with highly electron-withdrawing end-capping groups passivates GBs and boosts perovskite grain growth. This effective defect passivation decreases the trap density to increase the carrier recombination lifetime of the perovskite film. As a result, bromo-substituted dicyanomethylene indanone (INBr)-end-capped BCDT (INBrBCDT-b8; 3a)-passivated devices exhibit the highest power conversion efficiency (PCE) of 22.20% (vs those of 18.09% obtained for perovskite films without passivation) upon an optimized film preparation process. Note that devices treated with more soluble 2-ethylhexyl-substituted compounds (1a, 2a, and 3a) exhibit higher PCE than those treated with less soluble octyl-substituted compounds (1b, 2b, and 3b). It is also worth noting that BCDT is a cost-effective six-ring core that is easier to synthesize with a higher yield and therefore much cheaper than those with highly fused-ring cores. In addition, a long-term stability test in a glovebox for 1500 h reveals that the perovskite solar cells (PSCs) based on a perovskite absorber treated with compound 3a maintain ∼90% of their initial PCE. This is the first example of the simplest high-conjugation additive for perovskite film to achieve a PCE greater than 22% of the corresponding lead-based PSCs.

Natural protoberberine alkaloid-montmorillonite nanocomposite powders with AIE features for visualizing high-resolution latent fingerprints.

Real-time and in-situ fluorescence visualization technologies have attention to in the forensic analysis of latent fingerprints (LFPs). The fingerprint powders with high performance and biocompatibility are essential for imaging LFPs with high definition and safety. In this work, five quaternary protoberberine alkaloid (QPA) derivatives were analyzed with reorganization energy and four-point calculations to explain the relationship between the substituent effect and luminescent properties and further resolve the luminous behaviors of four QPA-based natural products in solution. Thanks to the restriction of the intramolecular motions mechanism, aggregation-induced emission (AIE) active BBC nanoaggregates could sensitively detect explosive analog, 2,4,6-trinitrophenol, at a nanomolar level (9.8 nM of detection limit). Combined with natural montmorillonite (MMT) mineral powders, three levels of details for fingerprints were successfully imaged with solid-luminous BBC/MMT nanocomposites. The insight into the substituted effect of alkoxy groups on the QPA framework not only provides a new concept to design rotor-free AIE luminogens but also expands natural products and their nanocomposites into LFP and detection applications.

Dopant-Free Pyrrolopyrrole-Based (PPr) Polymeric Hole-Transporting Materials for Efficient Tin-Based Perovskite Solar Cells with Stability Over 6000 h.

A new set of pyrrolopyrrole-based (PPr) polymers incorporated with thioalkylated/alkylated bithiophene (SBT/BT) is synthesized and explored as hole-transporting materials (HTMs) for Sn-based perovskite solar cells (TPSCs). Three bithiophenyl spacers bearing the thioalkylated hexyl (SBT-6), thioalkylated tetradecyl (SBT-14), and tetradecyl (BT-14) chains are utilized to examine the effect of the alkyl chain lengths. Among them, the TPSCs are fabricated using PPr-SBT-14 as HTMs through a two-step approach by attaining a power conversion efficiency (PCE) of 7.6% with a remarkable long-term stability beyond 6000 h, which has not been reported elsewhere for a non-PEDOT:PSS-based TPSC. The PPr-SBT-14 device is stable under light irradiation for 5 h in air (50% relative humidity) at the maximum power point (MPP). The highly planar structure, strong intramolecular S(alkyl)···S(thiophene) interactions, and extended π-conjugation of SBT enable the PPr-SBT-14 device to outperform the standard poly(3-hexylthiophene,-2,5-diyl (P3HT) and other devices. The longer thio-tetradecyl chain in SBT-14 restricts molecular rotation and strongly affects the molecular conformation, solubility, and film wettability over other polymers. Thus, the present study makes a promising dopant-free polymeric HTM model for the future design of highly efficient and stable TPSCs.

Triarylamine-Functionalized Imidazolyl-Capped Bithiophene Hole Transporting Material for Cost-Effective Perovskite Solar Cells.

Triarylamine end-capped-functionalized arylene-imidazole derivatives were synthesized from readily accessible, inexpensive precursors and employed as hole transporting materials (HTMs) in perovskite solar cells (PSCs). All the HTMs displayed high thermal decomposition temperatures (>410 °C), which is beneficial for realizing stable PSC devices. In addition, the new HTMs show appropriate energy level alignment with the perovskite layer, ensuring efficient hole transfer from perovskites to HTMs. Interestingly, PSCs fabricated with the triarylamine-functionalized imidazolyl-capped bithiophene molecule (DImBT-4D) as the HTM exhibited the best power conversion efficiency of 20.11%, comparable to that of the benchmark HTM spiro-OMeTAD, prompting it be a prospective candidate for large-scale PSC applications.

Monitoring tumor growth with a novel NIR-II photoacoustic probe.

In this chapter, we designed and synthesized a series of thiadiazoloquinoxaline (TQ)-based semiconducting polymers (SPs) with a broad absorption covering from NIR-I to NIR-II regions. Theoretical calculation suggests that the BTD-TQE with ester-substituted TQ-acceptor shows a large dihedral angle and narrow adiabatic energy as well as low radiative decay, resulting in higher reorganization energy for efficient photoinduced nonradiative decay (PNRD). As a result, the obtained BDT-TQE SP-cored nanoparticles, a NIR-II PA probe, exhibit a highest NIR-II photothermal conversion efficiency (61.6%) and achieved PA tracking of in situ hepatic tumor growth for 20 days. Herein, we propose a strategy to construct an effective NIR-II photoacoustic reagent through the enhanced PNRD effect of twisted intramolecular charge transfer (TICT), thereby extending the application of NIR-II PA reagents in in vivo bioimaging.

Self-assembled AIEgen nanoparticles for multiscale NIR-II vascular imaging.

In the recent decades, fluorogens with aggregation-induced emission (AIEgens) have been intensively explored in biomedical applications. One main strategy to bring these hydrophobic AIEgens into the aqueous biological environment is to encapsulate them in nanoparticles with functionalized polymeric matrices. However, exploration of reliable strategies that can afford AIE nanoparticles with uniform size and stable loading efficiency with minimized variation still remains a challenge. Here, we rationally designed amphiphilic AIEgens, constructed by a hydrophobic donor-acceptor-donor (D-A-D) core and hydrophilic polyethylene glycol (PEG) chain. The afforded amphiphilic AIEgens can self-assemble into uniform nanoparticles with average sizes of ~35 nm, showing an emission maximum beyond 1000 nm and quantum yields (QYs) above 10%. We then used the bright AIE nanoparticles for multiscale intravital vascular fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) in mouse and rabbit models with a high-resolution of ~38 µm and a penetration depth of ~1 cm. As such, our results demonstrate an efficient self-assembly strategy to construct advanced AIE nanoparticles for angiography.

Acceptor engineering of small-molecule fluorophores for NIR-II fluorescence and photoacoustic imaging.

Fluorescence imaging in the second near-infrared window (NIR-II) has been an emerging technique in diverse in vivo applications with high sensitivity/resolution and deep tissue penetration. To date, the design principle of the reported NIR-II organic fluorophores has heavily relied on benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole) (BBTD) as a strong electron acceptor. Here, we report the rational design and synthesis of a NIR-II fluorescent molecule with the rarely used [1,2,5]thiadiazolo[3,4-f]benzotriazole (TBZ) core to replace BBTD as the electron acceptor. Thanks to the weaker electron deficiency of the TBZ core than BBTD, the newly yielded NIR-II molecule (BTB) based nanoparticles have a higher mass extinction coefficient and quantum yield in water. In contrast, the nanoparticle suspension of its counterpart with BBTD as the core is nearly nonemissive. The NIR-II BTB nanoparticles allow video-rate fluorescence imaging for vasculature imaging in ears, hindlimbs, and the brain of the mouse. Additionally, its large absorptivity in the NIR-I region also promotes bioimaging using photoacoustic microscopy (PAM) and tomography (PAT). Upon surface conjugation with the Arg-Gly-Asp (RGD) peptide, the functionalized nanoparticles ensured targeted detection of integrin-overexpressed tumors through both imaging modalities in two- and three-dimensional views. Thus, our approach to engineering acceptors of organic fluorophores offers a promising molecular design strategy to afford new NIR-II fluorophores for versatile biomedical imaging applications.

Type I macrophage activator photosensitizer against hypoxic tumors.

Photodynamic immunotherapy has emerged as a promising strategy to treat cancer. However, the hypoxic nature of most solid tumors and notoriously immunosuppressive tumor microenvironment could greatly compromise the efficacy of photodynamic immunotherapy. To address this challenge, we rationally synthesized a type I photosensitizer of TPA-DCR nanoparticles (NPs) with aggregation-enhanced reactive oxygen species generation via an oxygen-independent pathway. We demonstrated that the free radicals produced by TPA-DCR NPs could reprogram M0 and M2 macrophages into an anti-tumor state, which is not restricted by the hypoxic conditions. The activated M1 macrophages could further induce the immunogenic cell death of cancer cells by secreting pro-inflammatory cytokines and phagocytosis. In addition, in vivo anti-tumor experiments revealed that the TPA-DCR NPs could further trigger tumor immune response by re-educating tumor-associated macrophages toward M1 phenotype and promoting T cell infiltration. Overall, this work demonstrates the design of type I organic photosensitizers and mechanistic investigation of their superior anti-tumor efficacy. The results will benefit the exploration of advanced strategies to regulate the tumor microenvironment for effective photodynamic immunotherapy against hypoxic tumors.

Photoacoustic Force-Guided Precise and Fast Delivery of Nanomedicine with Boosted Therapeutic Efficacy.

Precise and efficient delivery of nanomedicine to the target site has remained as a major roadblock in advanced cancer treatment. Here, a novel photoacoustic force (PAF)-guided nanotherapeutic system is reported based on a near-infrared (NIR)-absorbing semiconducting polymer (SP), showing significantly improved tumor accumulation and deep tissue penetration for enhanced phototherapeutic efficacy. The accumulation of nanoparticles in 4T1 tumor-bearing mice induced by the PAF strategy displays a fivefold enhancement in comparison with that of the traditional passive targeting pathway, in a significantly shortened time (45 min vs 24 h) with an enhanced penetration depth in tumors. Additionally, a tumor-bearing mouse model is rationally designed to unveil the mechanism, indicating that the nanoparticles enter solid tumors through enhanced transportation across blood vessel barriers via both inter-endothelial gaps and active trans-endothelial pathways. This process is specifically driven by PAF generated from the nanoparticles under NIR laser irradiation. The study thus demonstrates a new nanotherapeutic strategy with low dose, enhanced delivery efficiency in tumor, and boosted therapeutic efficacy, opening new doors for designing novel nanocarriers.