Neutral Cyanine: Ultra-Stable NIR-II Merocyanines for Highly Efficient Bioimaging and Tumor-Targeted Phototheranostics.

Fluorescence imaging (FLI)-guided phototheranostics using emission from the second near-infrared (NIR-II) window show significant potential for cancer diagnosis and treatment. Clinical imaging-used polymethine ionic indocyanine green (ICG) dye is widely adopted for NIR fluorescence imaging-guided photothermal therapy (PTT) research due to its exceptional photophysical properties. However, ICG has limitations such as poor photostability, low photothermal conversion efficiency (PCE), short-wavelength emission peak, and liver-targeting issues, which restrict its wider use. In this study, two ionic ICG derivatives are transformed into neutral merocyanines (mCy) to achieve much-enhanced performance for NIR-II cancer phototheranostics. Initial designs of two ionic dyes show similar drawbacks as ICG in terms of poor photostability and low photothermal performance. One of the modified neutral molecules, mCy890, shows significantly improved stability, an emission peak over 1000 nm, and a high photothermal PCE of 51%, all considerably outperform ICG. In vivo studies demonstrate that nanoparticles of the mCy890 can effectively accumulate at the tumor sites for cancer photothermal therapy guided by NIR-II fluorescence imaging. This research provides valuable insights into the development of neutral merocyanines for enhanced cancer phototheranostics.

A Nanographene-Porphyrin Hybrid for Near-Infrared-Ii Phototheranostics.

Photoacoustic imaging (PAI)-guided photothermal therapy (PTT) in the second near-infrared (NIR-II, 1000-1700 nm) window has been attracting attention as a promising cancer theranostic platform. Here, it is reported that the π-extended porphyrins fused with one or two nanographene units (NGP-1 and NGP-2) can serve as a new class of NIR-responsive organic agents, displaying absorption extending to ≈1000 and ≈1400 nm in the NIR-I and NIR-II windows, respectively. NGP-1 and NGP-2 are dispersed in water through encapsulation into self-assembled nanoparticles (NPs), achieving high photothermal conversion efficiency of 60% and 69%, respectively, under 808 and 1064 nm laser irradiation. Moreover, the NIR-II-active NGP-2-NPs demonstrated promising photoacoustic responses, along with high photostability and biocompatibility, enabling PAI and efficient NIR-II PTT of cancer in vivo.

Ultra-efficient delivery of CRISPR/Cas9 using ionic liquid conjugated polymers for genome editing-based tumor therapy.

Emerging CRISPR-Cas9 systems can rebuild DNA sequences in the genome in a spatiotemporal manner, offering a magic tool for biological research, drug discovery, and gene therapy. However, low delivery efficiency remains a major roadblock hampering the wide application of CRISPR-Cas9 gene editing talent. Herein, ionic liquid-conjugated polymers (IL-CPs) are explored as efficient platforms for CRISPR-Cas9 plasmid delivery and in vivo genome editing-based tumor therapy. Via molecular screening of IL-CPs, IL-CPs integrated with fluorination monomers (PBF) can encapsulate plasmids into hybrid nanoparticles and achieve over 90% delivery efficiency in various cells regardless of serum interference. In vitro and in vivo experiments demonstrate that PBF can mediate Cas9/PLK1 plasmids for intracellular delivery and therapeutic genome editing in tumor, achieving efficient tumor suppression. This work provides a new tool for safe and efficient CRISPR-Cas9 delivery and therapeutic genome editing, thus opening a new avenue for the development of ionic liquid polymeric vectors for genome editing and therapy.

Recent strategies for evoking immunogenic Pyroptosis in antitumor immunotherapy.

Pyroptosis is a specific type of programmed cell death (PCD) characterized by distinct morphological changes, including cell swelling, membrane blebbing, DNA fragmentation, and eventual cell lysis. Pyroptosis is closely associated with human-related diseases, such as inflammation and malignancies. Since the initial observation of pyroptosis in Shigella flexneri-infected macrophages more than 20 years ago, various pyroptosis-inducing agents, including ions, small molecules, and biological nanomaterials, have been developed for tumor treatment. Given that pyroptosis can activate the body's robust immune response against tumor and promote the formation of the body's long-term immune memory in tumor treatment, its status as a type of immunogenic cell death is self-evident. Therefore, pyroptosis should be used as a powerful anti-tumor strategy. However, there still is a lack of a comprehensive summary of the most recent advances in pyroptosis-based cancer therapy. Therefore, it is vital to fill this gap and inspire future drug design to better induce tumor cells to undergo pyroptosis to achieve advanced anti-tumor effects. In this review, we summarize in detail the most recent advances in triggering tumor cell immunogenic pyroptosis for adequate tumor clearance based on various treatment modalities, and highlight material design and therapeutic advantages. Besides, we also provide an outlook on the prospects of this emerging field in the next development.

A Stable Open-Shell Conjugated Diradical Polymer with Ultra-High Photothermal Conversion Efficiency for NIR-II Photo-Immunotherapy of Metastatic Tumor.

Massive efforts have been concentrated on the advance of eminent near-infrared (NIR) photothermal materials (PTMs) in the NIR-II window (1000-1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-II-responsive organic PTMs was explored, and their photothermal conversion efficiencies (PCEs) still remain relatively low. Herein, donor-acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-II window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-II absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-II light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-II window, without any side-effect. Moreover, by combining with PD-1 antibody, the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-II window, offering a new horizon in developing radical-characteristic NIR-II photothermal materials.

Selenium-integrated conjugated oligomer nanoparticles with high photothermal conversion efficiency for NIR-II imaging-guided cancer phototheranostics in vivo.

Second near-infrared (NIR-II) fluorescence imaging in the range of 1000-1700 nm has great prospects for in vivo imaging and theranostics monitoring. At present, few NIR-II probes with theranostics properties have been developed, especially the high-performance organic theranostics material remains underexploited. Herein, we demonstrate a selenium (Se)-tailoring method to develop high-efficient NIR-II imaging-guided material for in vivo cancer phototheranostics. Via Se-tailoring strategy, conjugated oligomer TPSe-based nanoparticles (TPSe NPs) achieve bright NIR-II emission up to 1400 nm and exhibit a relatively high photothermal conversion efficiency of 60% with good stability. Moreover, the TPSe NPs demonstrate their photothermal ablation of cancer cells in vitro and tumor in vivo with the guidance of NIR-II imaging. It is worth noting that the TPSe NPs have good biocompatibility without obvious side effects. Thus, this work provides new insight into the development of NIR-II theranostics agents.

NIR-II Regulation of Mitochondrial Potassium Channel with Dual-Targeted Conjugated Oligomer Nanoparticles for Efficient Cancer Theranostics In Vivo.

Cell fate can be efficiently modulated by switching ion channels. However, the precise regulation of ion channels in cells, especially in specific organelles, remains challenging. Herein, biomimetic second near-infrared (NIR-II) responsive conjugated oligomer nanoparticles with dual-targeted properties are designed and prepared to modulate the ion channels of mitochondria to selectively kill malignant cells in vivo. Upon 1060 nm laser irradiation, the mitochondria-located nanoparticles photothermally release a specific ion inhibitor of the potassium channel via a temperature-sensitive liposome, thus altering the redox balance and pathways of mitochondria. NIR-II responsive nanoparticles can effectively regulate the potassium channels of mitochondria and fully suppress tumor growth. This work provides a new modality based on the NIR-II nanoplatform to regulate ion channels in specific organelles and proposes an effective therapeutic mechanism for malignant tumors.

Recent Progress of Preparation Strategies in Organic Nanoparticles for Cancer Phototherapeutics.

Phototherapy has the advantages of being a highly targeted, less toxic, less invasive, and repeatable treatment, compared with conventional treatment methods such as surgery, chemotherapy, and radiotherapy. The preparation strategies are significant in order to determine the physical and chemical properties of nanoparticles. However, choosing appropriate preparation strategies to meet applications is still challenging. This review summarizes the recent progress of preparation strategies in organic nanoparticles, mainly focusing on the principles, methods, and advantages of nanopreparation strategies. In addition, typical examples of cancer phototherapeutics are introduced in detail to inform the choice of appropriate preparation strategies. The relative future trend and outlook are preliminarily proposed.

NIR-II fluorescence and PA imaging guided activation of STING pathway in photothermal therapy for boosting cancer immunotherapy by theranostic thermosensitive liposomes.

Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cell (DC) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost the adaptive anti-tumor immunity of photothermal immunotherapy and to achieve multiple bioimaging modalities in a real-time manner. PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cell maturation and T cell recruitment. Moreover, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.

Dual-Pronged Attack: pH-Driven Membrane-Anchored NIR Dual-Type Nano-Photosensitizer Excites Immunogenic Pyroptosis and Sequester Immune Checkpoint for Enhanced Prostate Cancer Photo-Immunotherapy.

Prostate cancer (PCa) is a frustrating immunogenic "cold" tumor and generally receives unsatisfied immunotherapy outcomes in the clinic. Pyroptosis is an excellent immunogenic cell death form that can effectively activate the antitumor immune response, promote cytotoxic T-lymphocyte infiltration, and convert tumors from "cold" to "hot." However, the in vivo application of pyroptosis drugs is seriously limited, and the upregulation of tumor PD-L1 caused by photo-immunotherapy further promotes immune escape. Herein, a new nano-photosensitizer (YBS-BMS NPs-RKC) with pH-response integrating immunogenic pyroptosis induction and immune checkpoint blockade is developed. The pH-responsive polymer equipped with the cell membrane anchoring peptide RKC is used as the carrier and further encapsulated with the near-infrared-activated semiconductor polymer photosensitizer YBS and a PD-1/PD-L1 complex small molecule inhibitor BMS-202. The pH-driven membrane-anchoring and pyroptosis activation of YBS-BMS NPs-RKC is clearly demonstrated. In vitro and in vivo studies have shown that this dual-pronged therapy stimulates a powerful antitumor immune response to suppress primary tumor progression and evokes long-term immune memory to inhibit tumor relapse and metastasis. This work provides an effective self-synergistic platform for PCa immunotherapy and a new idea for developing more biocompatible photo-controlled pyroptosis inducers.

Anti-Quenching NIR-II J-Aggregates of Benzo[c]thiophene Fluorophore for Highly Efficient Bioimaging and Phototheranostics.

Molecular fluorophores with the second near-infrared (NIR-II) emission hold great potential for deep-tissue bioimaging owing to their excellent biocompatibility and high resolution. Recently, J-aggregates are used to construct long-wavelength NIR-II emitters as their optical bands show remarkable red shifts upon forming water-dispersible nano-aggregates. However, their wide applications in the NIR-II fluorescence imaging are impeded by the limited varieties of J-type backbone and serious fluorescence quenching. Herein, a bright benzo[c]thiophene (BT) J-aggregate fluorophore (BT6) with anti-quenching effect is reported for highly efficient NIR-II bioimaging and phototheranostics. The BT fluorophores are manipulated to have Stokes shift over 400 nm and aggregation-induced emission (AIE) property for conquering the self-quenching issue of the J-type fluorophores. Upon forming BT6 assemblies in an aqueous environment, the absorption over 800 nm and NIR-II emission over 1000 nm are boosted for more than 41 and 26 folds, respectively. In vivo visualization of the whole-body blood vessel and imaging-guided phototherapy results verify that BT6 NPs are excellent agent for NIR-II fluorescence imaging and cancer phototheranostics. This work develops a strategy to construct bright NIR-II J-aggregates with precisely manipulated anti-quenching properties for highly efficient biomedical applications.

Remote Manipulation of ROS-Sensitive Calcium Channel Using Near-Infrared-Responsive Conjugated Oligomer Nanoparticles for Enhanced Tumor Therapy In Vivo.

The regulation of reactive oxygen species (ROS)-sensitive calcium (Ca2+) channels is of great significance in the treatment of tumors. Here, a simple ROS generation system is developed to activate ROS-sensitive ion channels for enhancing calcium-cascade-mediated tumor cell death under near-infrared (NIR) light irradiation. Upon irradiation with an 808 nm laser, a low-lethality amount of ROS facilitates plasmid transient potential receptor melastatin-2 (pTRPM2) gene release via cleavage of the Se-Se bonds, which contributed to enhancing the expression of TRPM2 in tumor cells. Meanwhile, ROS could potently activate TRPM2 for Ca2+ influx to inhibit early autophagy and to further induce intracellular ROS production, which ultimately led to cell death in TRPM2 expressing tumor cells. Both in vitro and in vivo data show that nanoparticles have an excellent therapeutic effect on cancer upon NIR light. This work presents a simple modality based on NIR light to remotely control the ROS-sensitive ion channel for cancer therapy.

An Enhanced Photothermal Therapeutic Iridium Hybrid Platform Reversing the Tumor Hypoxic Microenvironment.

As hypoxia is closely associated with tumor progression, proliferation, invasion, metastasis, and strong resistance to therapy, regulating and overcoming the hypoxia tumor microenvironment are two increasingly important aspects of tumor treatment. Herein, we report a phototherapeutic platform that uses the organic photosensitizer diketopyrrolopyrrole (DPP) derivative and inorganic iridium salts (IrCl3) with photothermal activity and the capacity to decompose H2O2 efficiently. The characterization of their photophysical properties proved that DPP-Ir nanoparticles are capable of remarkable near-infrared (NIR) absorption, and compared to DPP nanoparticles, the photothermal conversion efficiency (PCE) increases from 42.1% in DPP nanoparticles to 67.0% in DPP-Ir nanoparticles. The hybrid nanoparticles utilize the catalytic decomposition of endogenous H2O2 to produce oxygen for the downregulation of the hypoxia-inducible factor 1 subunit alpha (HIF-1α) protein, which could reverse the tumor hypoxic microenvironment. Benefiting from the excellent optical properties and good biocompatibility, the hybrid platform exhibits efficient photothermal therapeutic effects as well as good biological safety. In conclusion, such a hybrid platform could improve photothermal therapy against cancer.

Amplifying Free Radical Generation of AIE Photosensitizer with Small Singlet-Triplet Splitting for Hypoxia-Overcoming Photodynamic Therapy.

Type-I photodynamic therapy (PDT) with less oxygen consumption shows great potential for overcoming the vicious hypoxia typically observed in solid tumors. However, the development of type-I PDT is hindered by insufficient radical generation and the ambiguous design strategy of type-I photosensitizers (PSs). Therefore, developing highly efficient type-I PSs and unveiling their structure-function relationship are still urgent and challenging. Herein, we develop two phenanthro[9,10-d]imidazole derivatives (AQPO and AQPI) with aggregation-induced emission (AIE) characteristics and boost their reactive oxygen species (ROS) generation efficiency by reducing singlet-triplet splitting (ΔEST). Both AQPO and AQPI show ultrasmall ΔEST values of 0.09 and 0.12 eV, respectively. By incorporating electron-rich anisole, the categories of generated ROS by AIE PSs are changed from type-II (singlet oxygen, 1O2) to type-I (superoxide anion radical, O2•- and hydroxyl radical, •OH). We demonstrate that the assembled AQPO nanoparticles (NPs) achieve a 3.2- and 2.9-fold increase in the O2•- and •OH generation efficiencies, respectively, compared to those of AQPI NPs (without anisole) in water, whereas the 1O2 generation efficiency of AQPO NPs is lower (0.4-fold) than that of AQPI NPs. The small ΔEST and anisole group endow AQPO with an excellent capacity for type-I ROS generation. In vitro and in vivo experiments show that AQPO NPs achieve an excellent hypoxia-overcoming PDT effect by efficiently eliminating tumor cells upon white light irradiation with good biosafety.

Carrier-Free Delivery of Ultrasmall π-Conjugated Oligomer Nanoparticles with Photothermal Conversion over 80% for Cancer Theranostics.

High-performance photothermal theranostics is urgently desired for cancer therapy because of their good controllability and noninvasive features. The relatively low photothermal conversion efficiency is still at the drawbacks because of the absence of efficient extraneous carriers. Herein, a carrier-free nanomedicine is developed to in vivo self-deliver organic photothermal agents for efficient cancer phototheranostics. By a facile self-assembly strategy, the near-infrared (NIR)-absorbing conjugated oligomer IDIC-4F is fabricated into a carrier-free nanoparticle (DCF-P), showing ultrasmall size of nearly 4.0 nm with a nearly 100% of drug loading capacity. Notably, DCF-P achieves a superhigh photothermal conversion efficiency of 80.5% that is far greater than that of IDIC-4F-loaded nanomicelle DCF-M (57.3%). With the guidance of NIR fluorescence and photoacoustic dual-imaging, it is verified that DCF-P could well achieve tumor-preferential accumulation and retention at 4 h postinjection, and meanwhile shows highly efficient in vivo tumor elimination with good biosafety. This study thus contributes a novel concept for designing ultrasmall nanoparticle characteristics of preferential accumulation in tumors, and also provides a strategy for creating high-performance carrier-free nanomedicine via highly ordered molecular stacking.

Electrochemical detection of methyl-paraoxon based on bifunctional cerium oxide nanozyme with catalytic activity and signal amplification effect.

A new electrochemical sensor for organophosphate pesticide (methyl-paraoxon) detection based on bifunctional cerium oxide (CeO2) nanozyme is here reported for the first time. Methyl-paraoxon was degraded into p-nitrophenol by using CeO2 with phosphatase mimicking activity. The CeO2 nanozyme-modified electrode was then synthesized to detect p-nitrophenol. Cyclic voltammetry was applied to investigate the electrochemical behavior of the modified electrode, which indicates that the signal enhancement effect may attribute to the coating of CeO2 nanozyme. The current research also studied and discussed the main parameters affecting the analytical signal, including accumulation potential, accumulation time, and pH. Under the optimum conditions, the present method provided a wider linear range from 0.1 to 100 µmol/L for methyl-paraoxon with a detection limit of 0.06 µmol/L. To validate the proof of concept, the electrochemical sensor was then successfully applied for the determination of methyl-paraoxon in three herb samples, i.e., Coix lacryma-jobi, Adenophora stricta and Semen nelumbinis. Our findings may provide new insights into the application of bifunctional nanozyme in electrochemical detection of organophosphorus pesticide.

Stable π-radical nanoparticles as versatile photosensitizers for effective hypoxia-overcoming photodynamic therapy.

We report the first demonstration using a stable π-radical as a versatile photosensitizer for hypoxia-overcoming photodynamic therapy. After self-assembling the radical molecules into radical nanoparticles (NPs), the NPs show good water dispersibility, good biocompatibility, broad near-infrared (NIR) absorption and emission at ∼800 nm. Significantly, the radical NPs remain stable in various biological mediums, after 100 days exposure to the ambient environment, and even after long-term laser irradiation, which is superior to many reported radical-based materials. More importantly, upon 635 nm laser irradiation, sufficient superoxide radical (O2-˙) generation and in vitro cytotoxicity were observed addressing the most important hurdle for successful PDT in the oxygen-deficient tumor microenvironment. In addition, the radical NPs are also demonstrated to have effective in vivo PDT efficacy, and excellent biosafety.

Recent Advances in Hypoxia-Overcoming Strategy of Aggregation-Induced Emission Photosensitizers for Efficient Photodynamic Therapy.

Hypoxia is an inherent physiologic barrier in the microenvironment of solid tumor and has badly restricted the therapeutic effect of photodynamic therapy (PDT). Meanwhile, the photosensitizer (PS) agents used for PDT applications regularly encounter the tiresome aggregation-caused quenching effect that seriously decreases the production efficiency of cytotoxic reactive oxygen species. The aggregation-induced emission (AIE) PSs with antiquenching characteristics in the aggregate state are considered as a promising tool for achieving highly efficient PDT applications, and plenty of studies have widely demonstrated their advantages in various diseases. Herein, the recent progress of AIE PSs in the battle of antitumor hypoxia issue is summarized and the practical molecular principles of hypoxia-overcoming AIE PSs are highlighted. According to the hypoxia-overcoming mechanism, these representative cases are divided into low O2 -dependent (type I PDT) and O2 -dependent tactics (mainly including O2 -enrichment type II PDT and combination therapy). Furthermore, the underlying challenges and prospects of AIE PSs in hypoxia-overcoming PDT are proposed and thus expect to promote the next development of AIE PSs.

Conjugated Polymers: Optical Toolbox for Bioimaging and Cancer Therapy.

Conjugated polymers (CPs) are capable of coordinating the electron coupling phenomenon to bestow powerful optoelectronic features. The light-harvesting and light-amplifying properties of CPs are extensively used in figuring out the biomedical issues with special emphasis on accurate diagnosis, effective treatment, and precise theranostics. This review summarizes the recent progress of CP materials in bioimaging, cancer therapeutics, and introduces the design strategies by rationally tuning the optical properties. The recent advances of CPs in bioimaging applications are first summarized and the challenges to clear the future directions of CPs in the respective area are discussed. In the following sections, the focus is on the burgeoning applications of CPs in phototherapy of the tumor, and illustrates the underlying photo-transforming mechanism for further molecular designing. Besides, the recent progress in the CPs-assistant drug therapy, mainly including drug delivery, gene therapeutic, the optical-activated reversion of tumor resistance, and synergistic therapy has also been discussed elaborately. In the end, the potential challenges and future developments of CPs on cancer diagnosis and therapy are also illuminated for the improvement of optical functionalization and the promotion of clinical translation.

Photochemical Synthesis of Nonplanar Small Molecules with Ultrafast Nonradiative Decay for Highly Efficient Phototheranostics.

There has been much recent progress in the development of photothermal agents (PTAs) for biomedical and energy applications. Synthesis of organic PTAs typically involves noble metal catalysts and high temperatures. On the other hand, photochemical synthesis, as an alternative and green chemical technology, has obvious merits such as low cost, energy efficiency, and high yields. However, photochemical reactions have rarely been employed for the synthesis of PTAs. Herein, a facile and high-yield photochemical reaction is exploited for synthesizing nonplanar small molecules (NSMs) containing strong Michler's base donors and a tricyanoquinodimethane acceptor as high-performance PTAs. The synthesized NSMs show interesting photophysical properties including good absorption for photons of over 1000 nm wavelength, high near-infrared extinction coefficients, and excellent photothermal performance. Upon assembling the NSMs into nanoparticles (NSMN), they exhibit good biocompatibility, high photostability, and excellent photothermal conversion efficiency of 75%. Excited-state dynamic studies reveal that the NSMN has ultrafast nonradiative decay after photoexcitation. With these unique properties, the NSMN achieves efficient in vivo photoacoustic imaging and photothermal tumor ablation. This work demonstrates the superior potential of photochemical reactions for the synthesis of high-performance molecular PTAs.