Aromaticity Tuning of Heavy-Atom-Free Photosensitizers for Singlet Fission-Enhanced Immunogenic Photodynamic Oncotherapy.

The quantum yield of reactive oxygen species is of central importance for the development of organic photosensitizers and photodynamic therapy (PDT). A common molecular design approach for optimizing organic photosensitizers involves the incorporation of heavy atoms into their backbones. However, this raises concerns regarding heightened dark cytotoxicity and a shortened triplet-state lifetime. Herein, we demonstrate a heavy-atom-free (HAF) photosensitizer design strategy founded on the singlet fission (SF) mechanism for cancer PDT. Through the "single-atom surgery" approach to deleting oxygen atoms in pyrazino[2,3-g]quinoxaline skeleton photosensitizers, photosensitizers PhPQ and TriPhPQ are produced with Huckel's aromaticity and Baird's aromaticity in the ground state and triplet state, respectively, enabling the generation of two triplet excitons through SF. The SF process endows photosensitizer PhPQ with an ultrahigh triplet-state quantum yield (186%) and an outstanding 1O2 quantum yield (177%). Notably, HAF photosensitizers PhPQ and TriPhPQ enhanced PDT efficacy and potentiated αPD-L1 immune check blockade therapy in vivo, which show their promise for translational oncology treatment.

Stimuli-Actuated Turn-On Theranostic Nanoplatforms for Imaging-Guided Antibacterial Treatment.

Antibacterial theranostic nanoplatforms, which integrate diagnostic and therapeutic properties, exhibit gigantic application prospects in precision medicine. However, traditional theranostic nanoplatforms usually present an always-on signal output, which leads to poor specificity or selectivity in the treatment of bacterial infections. To address this challenge, stimuli-actuated turn-on nanoplatforms are developed for simultaneous activation of diagnostic signals (e.g., fluorescent, photoacoustic, magnetic signals) and initiation of antibacterial treatment. Specifically, by combining the infection microenvironment-responsive activation of visual signals and antibacterial activity, these theranostic nanoplatforms exert both higher accurate diagnosis rates and more effective treatment effects. In this review, the imaging and treatment strategies that are commonly used in the clinic are first briefly introduced. Next, the recent progress of stimuli-actuated turn-on theranostic nanoplatforms for treating bacterial infectious diseases is summarized in detail. Finally, current bottlenecks and future opportunities of antibacterial theranostic nanoplatforms are also outlined and discussed.

Recent Nanotechnologies to Overcome the Bacterial Biofilm Matrix Barriers.

Bacterial biofilm-related infectious diseases severely influence human health. Under typical situations, pathogens can colonize inert or biological surfaces and form biofilms. Biofilms are functional aggregates that coat bacteria with extracellular polymeric substances (EPS). The main reason for the failure of biofilm infection treatment is the low permeability and enrichment of therapeutic agents within the biofilm, which results from the particular features of biofilm matrix barriers such as negatively charged biofilm components and highly viscous compact EPS structures. Hence, developing novel therapeutic strategies with enhanced biofilm penetrability is crucial. Herein, the current progress of nanotechnology methods to improve therapeutic agents' penetrability against biofilm matrix, such as regulating material morphology and surface properties, utilizing the physical penetration of nano/micromotors or microneedle patches, and equipping nanoparticles with EPS degradation enzymes or signal molecules, is first summarized. Finally, the challenges, perspectives, and future implementations of engineered delivery systems to manage biofilm infections are presented in detail.

Direct Arylation Synthesis of Small Molecular Acceptors for Organic Solar Cells.

In recent years, small molecular acceptors (SMAs) have extensively promoted the progress of organic solar cells (OSCs). The facile tuning of chemical structures affords SMAs excellent tunability of their absorption and energy levels, and it gives SMA-based OSCs slight energy loss, enabling OSCs to achieve high power conversion efficiencies (e.g., >18%). However, SMAs always suffer complicated chemical structures requiring multiple-step synthesis and cumbersome purification, which is unfavorable to the large-scale production of SMAs and OSC devices for industrialization. Direct arylation coupling reaction via aromatic C-H bonds activation allows for the synthesis of SMAs under mild conditions, and it simultaneously reduces synthetic steps, synthetic difficulty, and toxic by-products. This review provides an overview of the progress of SMA synthesis through direct arylation and summarizes the typical reaction conditions to highlight the field's challenges. Significantly, the impacts of direct arylation conditions on reaction activity and reaction yield of the different reactants' structures are discussed and highlighted. This review gives a comprehensive view of preparing SMAs by direct arylation reactions to cause attention to the facile and low-cost synthesis of photovoltaic materials for OSCs.

NIR-II Organic Nanotheranostics for Precision Oncotherapy.

Precision oncotherapy can remove tumors without causing any apparent iatrogenic damage or irreversible side effects to normal tissues. Second near-infrared (NIR-II) nanotheranostics can simultaneously perform diagnostic and therapeutic modalities in a single nanoplatform, which exhibits prominent perspectives in tumor precision treatment. Among all NIR-II nanotheranostics, NIR-II organic nanotheranostics have shown an exceptional promise for translation in clinical tumor treatment than NIR-II inorganic nanotheranostics in virtue of their good biocompatibility, excellent reproducibility, desirable excretion, and high biosafety. In this review, recent progress of NIR-II organic nanotheranostics with the integration of tumor diagnosis and therapy is systematically summarized, focusing on the theranostic modes and performances. Furthermore, the current status quo, problems, and challenges are discussed, aiming to provide a certain guiding significance for the future development of NIR-II organic nanotheranostics for precision oncotherapy.

Type I Photosensitizers Revitalizing Photodynamic Oncotherapy.

Photodynamic therapy (PDT) has shown great potential for tumor treatment with merits of non-invasiveness, high selectivity, and minimal side effects. However, conventional type II PDT relying on 1 O2 presents poor therapeutic efficacy for hypoxic tumors due to the oxygen-dependent manner. Alternatively, emerging researches have demonstrated that type I PDT exhibits superiority over type II PDT in tumor treatment owing to its diminished oxygen-dependence. In this review, state-of-the-art studies concerning recent progress in type I photosensitizers are scrutinized, emphasizing the strategies to construct highly effective type I photosensitizers. As the foundation, basic principles of type I PDT are presented, and up-to-date type I photosensitizers are summarized and classified based on their attributes. Then, a literature review of representative type I photosensitizers (including nanomaterials and small molecules) is presented with impetus to delineate their novel designs, action mechanisms, as well as anticancer PDT applications. Finally, the remaining challenges and development directions of type I photosensitizers are outlined, highlighting key scientific issues toward clinical translations.

A Highly-Efficient Type I Photosensitizer with Robust Vascular-Disruption Activity for Hypoxic-and-Metastatic Tumor Specific Photodynamic Therapy.

Hypoxia severely impedes photodynamic therapy (PDT) efficiency. Worse still, considerable tumor metastasis will occur after PDT. Herein, an organic superoxide radical (O2∙- ) nano-photogenerator as a highly effcient type I photosensitizer with robust vascular-disrupting efficiency to combat these thorny issues is designed. Boron difluoride dipyrromethene (BODIPY)-vadimezan conjugate (BDPVDA) is synthesized and enwrapped in electron-rich polymer-brushes methoxy-poly(ethylene glycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) (mPEG- PPDA) to afford nanosized hydrophilic type I photosensitizer (PBV NPs). Owing to outstanding core-shell intermolecular electron transfer between BDPVDA and mPEG-PPDA, remarkable O2∙- can be produced by PBV NPs under near-infrared irradiation even in severe hypoxic environment (2% O2 ), thus to accomplish effective hypoxic-tumor elimination. Simultaneously, the efficient ester-bond hydrolysis of BDPVDA in the acidic tumor microenvironment allows vadimezan release from PBV NPs to disrupt vasculature, facilitating the shut-down of metastatic pathways. As a result, PBV NPs will not only be powerful in resolving the paradox between traditional type II PDT and hypoxia, but also successfully prevent tumor metastasis after type I PDT treatment (no secondary-tumors found in 70 days and 100% survival rate), enabling enhancement of existing hypoxic-and-metastatic tumor treatment.

Enhanced Tumor Penetration and Chemotherapy Efficiency by Covalent Self-Assembled Nanomicelle Responsive to Tumor Microenvironment.

The physicochemical properties of nanomedicine can be altered with a tumor microenvironment, which influence the precise delivery of drug molecules to the lesion. Thus, the therapeutic efficiency is restrained. Here, a covalent self-assembled nanomicelle (CSNM) based starburst polyprodrug was constructed with the unimolecular micelle-templated self-assembly method and was expected to overcome biological barriers. It aimed to enhance the tumor penetration and chemotherapy efficiency of drugs. In CSNM, a hydrophilic copolymer was glued around a camptothecin (CPT) linked starburst polymeric prodrug [ß-CD-P (CPT- co-NH2)] for protecting the positive charge of the prodrug with a reduction-triggered reversibility in conjugation and activity. Then, the complex was tracelessly delivered into a negatively charged cell membrane, leading to enhanced cellular uptake. Finally, the disulfide bond in the CPT prodrug can be broken under the reductive microenvironment within tumor cells and liberated the CPT molecules. Both in vitro and in vivo results demonstrated the benefits of our CSNM system, including high drug loading, controllable drug release, excellent uptake by tumor cells and remarkable antitumor efficiency. In essence, our findings suggested CSNM as an innovative strategy for drug delivery in chemotherapy, producing a competitive versatility in the development of biomedicine.

Organic Dye Based Nanoparticles for Cancer Phototheranostics.

Phototheranostics, which simultaneously combines photodynamic and/or photothermal therapy with deep-tissue diagnostic imaging, is a promising strategy for the diagnosis and treatment of cancers. Organic dyes with the merits of strong near-infrared absorbance, high photo-to-radical and/or photothermal conversion efficiency, great biocompatibility, ready chemical structure fine-tuning capability, and easy metabolism, have been demonstrated as attractive candidates for clinical phototheranostics. These organic dyes can be further designed and fabricated into nanoparticles (NPs) using various strategies. Compared to free molecules, these NPs can be equipped with multiple synergistic functions and show longer lifetime in blood circulation and passive tumor-targeting property via the enhanced permeability and retention effect. In this article, the recent progress of organic dye-based NPs for cancer phototheranostic applications is summarized, which extends the anticancer arsenal and holds promise for clinical uses in the near future.

Nano-black phosphorus for combined cancer phototherapy: recent advances and prospects.

Black phosphorus (BP), emerging as a new member of two-dimensional nanomaterials, has attracted growing research interests for its amazing photoelectric properties and promising application in electronic devices. Recently, BP has been confirmed to be a desirable candidate for phototherapy against cancer, including photothermal therapy and photodynamic therapy. By regulating the number of layers, the bandgap of BP nanosheets (NSs) can be finely tuned to present near infrared light triggered phototherapeutic behaviors. Furthermore, the exfoliated nano-sized BP also exhibits excellent tumor-targeting property as a nanomedicine via the enhanced permeability and retention effect. With biodegradable nature and outstanding therapeutic performance, BP is highly expected to be developed as novel anti-cancer agents as well as a potential carrier for advanced cancer theranostics. In this review, on the basis of summarizing the recent advances of BP in biomedical applications, the size and layer effects of BP on its targeting effect and phototherapeutic performance are discussed. Then, the rationally designed multifunctional nanoplatforms based on BP are introduced. And, the remaining challenges and prospects of nano-BP for clinic applications against cancer are discussed and outlooked.

S-Doped TiSe2 Nanoplates/Fe3 O4 Nanoparticles Heterostructure.

2D Sulfur-doped TiSe2 /Fe3 O4 (named as S-TiSe2 /Fe3 O4 ) heterostructures are synthesized successfully based on a facile oil phase process. The Fe3 O4 nanoparticles, with an average size of 8 nm, grow uniformly on the surface of S-doped TiSe2 (named as S-TiSe2 ) nanoplates (300 nm in diameter and 15 nm in thickness). These heterostructures combine the advantages of both S-TiSe2 with good electrical conductivity and Fe3 O4 with high theoretical Li storage capacity. As demonstrated potential applications for energy storage, the S-TiSe2 /Fe3 O4 heterostructures possess high reversible capacities (707.4 mAh g-1 at 0.1 A g-1 during the 100th cycle), excellent cycling stability (432.3 mAh g-1 after 200 cycles at 5 A g-1 ), and good rate capability (e.g., 301.7 mAh g-1 at 20 A g-1 ) in lithium-ion batteries. As for sodium-ion batteries, the S-TiSe2 /Fe3 O4 heterostructures also maintain reversible capacities of 402.3 mAh g-1 at 0.1 A g-1 after 100 cycles, and a high rate capacity of 203.3 mAh g-1 at 4 A g-1 .

Photophysical properties of octupolar triazatruxene-based chromophores.

The photophysical properties of three octupolar chromophores containing planar triazatruxene (TAT) as the central electron donor with different electron-withdrawing groups in the tribranched arrangement have been systematically investigated by means of steady state and transient spectroscopy. The multidimensional intramolecular charge transfer (ICT) properties of these tribranched chromophores related to the observed two-photon absorption (TPA) properties are explored by estimating the TPA essential factors (Mge and Δµge). Besides the large Stokes shift between steady state absorption and fluorescence spectra in different polar solvents, photoinduced ICT was further demonstrated by quantum-chemical calculations and transient absorption measurements. Both quantum calculations and spectral experiments show that a multidimensional ICT occurs from the electron-rich core to the electron-deficient periphery of these TAT derivatives. The results of solvation effects and the dynamics of the excited states show that the excited states of these three chromophores tend to exhibit an excitation localization on one of the dipolar branches, which is beneficial to achieve large Mge and Δµge, thus leading to enhanced TPA properties.

Planar-structured thiadiazoloquinoxaline-based NIR-II dye for tumor phototheranostics.

Second near-infrared (NIR-II) fluorescence imaging shows huge application prospects in clinical disease diagnosis and surgical navigation, while it is still a big challenge to exploit high performance NIR-II dyes with long-wavelength absorption and high fluorescence quantum yield. Herein, based on planar π-conjugated donor-acceptor-donor systems, three NIR-II dyes (TP-DBBT, TP-TQ1, and TP-TQ2) were synthesized with bulk steric hindrance, and the influence of acceptor engineering on absorption/emission wavelengths, fluorescence efficiency and photothermal properties was systematically investigated. Compared with TP-DBBT and TP-TQ2, the TP-TQ1 based on 6,7-diphenyl-[1,2,5]thiadiazoloquinoxaline can well balance absorption/emission wavelengths, NIR-II fluorescence brightness and photothermal effects. And the TP-TQ1 nanoparticles (NPs) possess high absorption ability at a peak absorption of 877 nm, with a high relative quantum yield of 0.69% for large steric hindrance hampering the close π-π stacking interactions. Furthermore, the TP-TQ1 NPs show a desirable photothermal conversion efficiency of 48% and good compatibility. In vivo experiments demonstrate that the TP-TQ1 NPs can serve as a versatile theranostic agent for NIR-II fluorescence/photoacoustic imaging-guided tumor phototherapy. The molecular planarization strategy provides an approach for designing efficient NIR-II fluorophores with extending absorption/emission wavelength, high fluorescence brightness, and outstanding phototheranostic performance.

Benzobisthiadiazole-Based Small Molecular Near-Infrared-II Fluorophores: From Molecular Engineering to Nanophototheranostics.

Organic fluorescent molecules with emission in the second near-infrared (NIR-II) biological window have aroused increasing investigation in cancer phototheranostics. Among these studies, Benzobisthiadiazole (BBT), with high electron affinity, is widely utilized as the electron acceptor in constructing donor-acceptor-donor (D-A-D) structured fluorophores with intensive near-infrared (NIR) absorption and NIR-II fluorescence. Until now, numerous BBT-based NIR-II dyes have been employed in tumor phototheranostics due to their exceptional structure tunability, biocompatibility, and photophysical properties. This review systematically overviews the research progress of BBT-based small molecular NIR-II dyes and focuses on molecule design and bioapplications. First, the molecular engineering strategies to fine-tune the photophysical properties in constructing the high-performance BBT-based NIR-II fluorophores are discussed in detail. Then, their biological applications in optical imaging and phototherapy are highlighted. Finally, the current challenges and future prospects of BBT-based NIR-II fluorescent dyes are also summarized. This review is believed to significantly promote the further progress of BBT-derived NIR-II fluorophores for cancer phototheranostics.

J-Aggregate Promoting NIR-II Emission for Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

J-aggregate is a promising strategy to enhance second near-infrared window (NIR-II) emission, while the controlled synthesis of J-aggregated NIR-II dyes is a huge challenge because of the lack of molecular design principle. Herein, bulk spiro[fluorene-9,9'-xanthene] functionalized benzobisthiadiazole-based NIR-II dyes (named BSFX-BBT and OSFX-BBT) are synthesized with different alkyl chains. The weak repulsion interaction between the donor and acceptor units and the S…N secondary interactions make the dyes to adopt a co-planar molecular conformation and display a peak absorption >880 nm in solution. Importantly, BSFX-BBT can form a desiring J-aggregate in the condensed state, and femtosecond transient absorption spectra reveal that the excited states of J-aggregate are the radiative states, and J-aggregate can facilitate stimulated emission. Consequently, the J-aggregated nanoparticles (NPs) display a peak emission at 1124 nm with a high relative quantum yield of 0.81%. The efficient NIR-II emission, good photothermal effect, and biocompatibility make the J-aggregated NPs demonstrate efficient antitumor efficacy via fluorescence/photoacoustic imaging-guided phototherapy. The paradigm illustrates that tuning the aggregate states of NIR-II dye via spiro-functionalized strategy is an effective approach to enhance photo-theranostic performance.

Correction: FDPP-HA as a theranostic agent for cancer-targeted fluorescence imaging and photodynamic therapy.

[This corrects the article DOI: 10.1039/C7RA06551E.].

Asymmetric aza-BODIPY photosensitizer for photoacoustic/photothermal imaging-guided synergistic photodynamic/photothermal therapy.

Cancer synergistic therapy usually shows improved therapeutic efficacy with low side effects. In this contribution, an aza-BODIPY-derived photosensitizer NBDP with asymmetric structure and the periphery phenyl ring modified with bromine atom was designed and synthesized for synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). Photosensitizer NBDP exhibited good singlet oxygen (1O2) generation capacity (1.43 times higher than that of ICG), and NBDP NPs showed an outstanding photothermal conversion efficiency (η) of 46.0% under 660 nm photoirradiation. Guided by in vivo photoacoustic (PA) imaging, NBDP NPs were found to targetedly accumulate in the tumor tissues in 6 h. All results showed that the aza-BODIPY-derived photosensitizer NBDP had great potential for PA/photothermal imaging-guided synergistic PTT/PDT.

Correction: Pyrrolopyrrole aza-BODIPY near-infrared photosensitizer for dual-mode imaging-guided photothermal cancer therapy.

Correction for 'Pyrrolopyrrole aza-BODIPY near-infrared photosensitizer for dual-mode imaging-guided photothermal cancer therapy' by Chaolong Wu et al., Chem. Commun., 2019, 55, 790-793, https://doi.org/10.1039/C8CC07768A.

Nanotherapeutics with immunoregulatory functions for the treatment of bacterial infection.

The advent of drug-resistant pathogens results in the occurrence of stubborn bacterial infections that cannot be treated with traditional antibiotics. Antibacterial immunotherapy by reviving or activating the body's immune system to eliminate pathogenic bacteria has confirmed promising therapeutic strategies in controlling bacterial infections. Subsequent studies found that antimicrobial immunotherapy has its own benefits and limitations, such as avoiding recurrence of infection and autoimmunity-induced side effects. Current studies indicate that the various antibacterial therapeutic strategies inducing immune regulation can achieve superior therapeutic efficacy compared with monotherapy alone. Therefore, summarizing the recent advances in nanomedicine with immunomodulatory functions for combating bacterial infections is necessary. Herein, we briefly introduce the crisis caused by drug-resistant bacteria and the opportunity for antibacterial immunotherapy. Then, immune-involved multimodal antibacterial therapy for the treatment of infectious diseases was systematically summarized. Finally, the prospects and challenges of immune-involved combinational therapy are discussed.