Tuberculosis presents a severe threat to human health. It is of crucial importance to develop novel and effective treatments to combat mycobacterial infections, especially those caused by drug-resistant bacteria. In this study, a tricarbonyl manganese(I) complex (Mn-PTP) was synthesized for the purpose of conducting synergistic therapy against mycobacterial infection. When subjected to white light irradiation, Mn-PTP generated multiple reactive species, including type I/II combined reactive oxygen species (ROS), carbon monoxide (CO), the toxic ligand PTP, and manganese oxides (MnOX) with catalase-like ability. The antibacterial experiment demonstrated that irradiated Mn-PTP exhibited specific antibacterial effects on Mycobacterium smegmatis (M. smegmatis). It was found to cause damage to the bacterial membrane and effectively eradicate biofilms. Moreover, the in vivo experiment revealed that the photoactive Mn-PTP could promote the healing process of M. smegmatis-infected skin wounds. This study pioneers innovative frameworks for developing one-for-all small-molecule pharmaceuticals capable of enabling synergistic therapeutic strategies against mycobacterial infections.

The development of antibiotic resistance has made multidrug-resistant bacterial and fungal infections one of the most serious health problems worldwide. Photothermal therapy (PTT) and photodynamic therapy (PDT) have received increasing attention in antimicrobial fields due to their precision treatment and less susceptibility to inducing resistance. In particular, developing second near-infrared (NIR-II, 1000-1700 nm)-emissive semiconducting polymers for phototheranostics is highly desirable but remains challenging due to the lack of rational molecular design guidelines. Herein, a precise side-chain engineering strategy based on donor-acceptor (D-A)-type semiconductor polymers is developed for antimicrobial phototherapy. By subtle regulation of the side-chain flexibility, a series of NIR-II-emissive polymer aggregation-induced-emission (AIE) luminogens (AIEgens) are constructed. The optimal polymer PIDT(He)TBT bearing flexible side chains shows optimal physicochemical properties, including the highest mass extinction coefficient, the best AIE property, red-shifted absorption/emission spectra, and desirable photodynamic and photothermal effects. PIDT(He)TBT is then encapsulated into nanoparticles to endow them with water solubility, excellent photostability, and enhanced type-I photodynamic and photothermal effects. The excellent performance of PIDT(He)TBT nanoparticles in terms of fluorescence-guided type-I PDT and PTT of bacterial and fungal infections has been demonstrated both in vitro and in vivo. This work brings useful insights into designing NIR-II-emissive semiconducting polymer AIEgens for highly efficient phototheranostics.

Organic near-infrared (NIR) photosensitizers (PS) largely facilitate photodynamic therapy (PDT). To overcome aggregation induced quenching and diminishment of reactive oxygen species (ROS) generation capability of NIR-PS, aggregation-induced emission (AIE) effect groups have been introduced to generate NIR AIE photosensitizers. However, currently reported NIR AIE photosensitizers all take "always-on" activity that may cause systemic phototoxic side effects. Tumor microenvironment activatable NIR AIE photosensitizers have not been reported. Here we develop an activatable NIR AIE PSnanoparticle (a-NA-PSNP) for near-infrared-II (NIR-II) fluorescence (FL) imaging-guided PDT under 808 nm excitation. NIR AIE photosensitizer (N-PS) is designed and frames with cysteine (Cys)/glutathione (GSH) responsive charge transfer complex (CTC) in bovine serum albumin (BSA) to obtain a-NA-PSNP. With the aggregated state in BSA, N-PS shows high quantum yield with good photostability. As an energy acceptor, CTC quenchs NIR-II fluorescence and ROS production capability of a-NA-PSNP in normal cells and tissues. CTC is decomposed in response to tumor microenvironment Cys/GSH, therefore recovers NIR-II fluorescence of a-NA-PSNP and efficiently generates ROS under 808 nm light irradiation. The depletion of Cys/GSH also regulates tumor intracellular reductive environment to further facilitate PDT. Both in vitro and in vivo results confirmed the tumor microenvironment selective and efficient activation of a-NA-PSNP, indicating its potential in cancer therapy.

Photo-immunotherapy is one of the most promising cancer treatment strategies. As immunotherapeutic agents, immune checkpoint blockade antibodies against programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) exhibit substantial potential, but have to face non-specific distribution and the subsequent immune-related adverse events. Meanwhile, high-performance phototheranostic agents concurrently possessing multiple phototheranostic modalities and high light-harvesting capacity are really attractive and highly desired as touching phototheranostic modules. Herein, a win-win strategy that integrates phototheranostic molecule design and targeted immunotherapeutic module preparation is developed to construct high-powered photo-immunotherapy systems. Specifically, the phototheranostic agent (AOTTIT) displaying typical aggregation-induced fluorescence extending to the second near-infrared II window, as well as outstanding reactive oxygen species and heat production capacity is first obtained via ingenious design. Notably, AOTTIT exhibits a record high molar extinction coefficient among the reported organic multimodal phototheranostic molecules. Meanwhile, PD-1 genetically engineered cancer cell membrane-derived nanovesicles (PD-1/CMNVs) are prepared as both nanocarriers and immunotherapeutic agents to camouflage AOTTIT nanoparticles, yielding a multifunctional photo-immunotherapeutic agent (CMNPs/PD-1) with tumor-specific active and homologous targeting ability. The distinct suppression of primary and metastatic lung tumors after only once treatment to the primary tumor substantiated the synergistically strengthened photo-immunotherapeutic efficiency of this win-win strategy.

Type-I photodynamic (PDT) and photothermal (PTT) synergistic therapy guided by fluorescence imaging in the near-infrared region II (NIR-II) is crucial for cancer diagnosis and treatment. Phototheranostics provide a promising system for efficient imaging-guided phototherapy, combining diagnostics with therapeutics within a single photosensitizer and avoiding the complexity of composition and low reproducibility of combination methods. Herein, we design and synthesize an all-in-one phototheranostic agent OTAB by modifying aza-BODIPY with a methoxy group substituted triphenylamine moiety, followed by the formation of nanoparticle OTAB@cRGD NPs via self-assembly with DSPE-PEG2000-cRGD. Structurally, the methoxy-modified triphenylamine moiety as a strong electron donor can reduce the singlet-triplet energy gap (ΔE S1-T1) by creating a strong intramolecular charge transfer state, thereby accelerating the intersystem crossing process and thus preferentially generating O2˙- via electron transfer. A single 808 nm laser can trigger its NIR-II imaging and excellent type-I photodynamic and photothermal therapy. Furthermore, OTAB@cRGD NPs with high photostability, colloid stability and biocompatibility can actively target tumor tissue via intravenous injection. Thus, tumor localization and imaging diagnosis are successfully realized. The PDT/PTT synergistic therapy brings efficient tumor inhibition and ablation both in vitro and in vivo. Therefore, this work provides a new strategy to construct an all-in-one multifunctional probe for the integration of NIR-II diagnosis and treatment.

Glioblastoma is the most common and devastating brain tumor owing to its high invasiveness and high-frequency drug resistance. Near infrared-II (NIR-II) imaging-guided phototherapy based on polymer luminogens provides a promising remedy against drug-resistant glioma, but it is difficult to maximize photoenergy utilization. Herein, we designed a series of semiconducting polymers to boost the visualization and ablation of glioblastoma. By subtly engineering the side chains or substituents on the phenothiazine and thiophene moieties, an NIR-II polymer luminogen with high-quality fluorescence performance, good solubility, superior photothermal conversion, and balanced reactive oxygen species generation is achieved. The optimal polymer possesses a branched alkyl chain and tetraphenylethylene pendant to manipulate the equilibrium between the radiative and nonradiative energy-dissipating channels. High-sensitivity NIR-II imaging was used to monitor the blood-brain barrier penetration and glioma cell targeting of apolipoprotein E-modified polymer nanoparticles. The NIR irradiation triggers and maximizes the photon utilization in prominent photodynamic/photothermal synergistic therapy in orthotopic drug-resistant glioblastoma.

The hypoxic environment of solid tumors significantly diminishes the therapeutic efficacy of oxygen-dependent photodynamic therapy. Developing efficient photosensitizers that operate via photoredox catalysis presents a promising strategy to overcome this challenge. Herein, we report the rational design of two rhenium(I) tricarbonyl complexes (Re-TPO and Re-TP) with electron donor-acceptor-donor configuration. Notably, Re-TP exhibits aggregation-induced emission properties and enhanced spin-orbit coupling compared to Re-TPO, thus exhibiting promoted photosensitizing capability. In addition to generating type I and II reactive oxygen species, the excited Re-TP facilitates the photocatalytic oxidation of NADH to NAD+ and the photoreduction of pyruvic acid to lactic acid. This metabolic intervention triggers PD-L1-linked immune responses and disrupts tumor redox balance, leading to ferroptosis and immunogenic cell death. The combined ferroptosis and immunotherapy effects significantly suppress both primary and distant B16 tumors. This investigation provides a compelling model for designing efficient metal-based PSs for photoredox-mediated photoimmunotherapy against hypoxic tumors.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising treatment options, showcasing immense potential in addressing both oncologic and nononcologic diseases. Single-component organic phototherapeutic agents (SCOPAs) offer advantages compared to inorganic or multicomponent nanomedicine, including better biosafety, lower toxicity, simpler synthesis, and enhanced reproducibility. Nonetheless, how to further improve the therapeutic effectiveness of SCOPAs remains a challenging research area. This review delves deeply into strategies to improve the performance of PDT or PTT by optimizing the structural design of SCOPAs. These strategies encompass augmenting reactive oxygen species (ROS) generation, mitigating oxygen dependence, elevating light absorption capacity, broadening the absorption region, and enhancing the photothermal conversion efficiency (PCE). Additionally, this review also underscores the ideal strategies for developing SCOPAs with balanced PDT and PTT. Furthermore, the potential synergies are highlighted between PDT and PTT with other treatment modalities such as ferroptosis, gas therapy, chemotherapy, and immunotherapy. By providing a comprehensive analysis of these strategies, this review aspires to serve as a valuable resource for clinicians and researchers, facilitating the wider application and advancement of SCOPAs-mediated PDT and PTT.

Exploiting single molecular species synchronously affording powerful second near-infrared (NIR-II) fluorescence, superior photoacoustic output, prominent reactive oxygen species generation, and satisfactory photothermal conversion is supremely appealing for phototheranostics, yet remains formidably challenging. In this work, electron donor/π-bridge engineering is implemented on the basis of 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazolo[3,4-g]quinoxaline moiety. The optimal molecule, namely TPATO-TTQ, is demonstrates to exhibit those notable features requested by exceptional phototheranostics, which are systematically elucidated through the depictions of excited-state energy dissipation pathways and the influence of intramolecular motion on the photophysical properties, with assistances of quantum chemical calculation and molecular dynamic simulation. By utilizing TPATO-TTQ nanoparticles, unprecedented performance on NIR-II fluorescence-photoacoustic-photothermal trimodal imaging-navigated type I photodynamic-photothermal synergistic therapy to orthotopic breast cancer is authenticates by the precise tumor diagnosis and complete tumor ablation.

Thermodynamic therapy (TDT) is a promising alternative to photodynamic therapy (PDT) by absorbing heat through thermosensitive agents (TSAs) to generate oxygen-irrelevant highly toxic free radicals. Therefore, TDT can be a perfect partner for photothermal therapy (PTT) to achieve efficient synergistic treatment of anoxic tumors using a single laser, greatly simplifying the treatment process and overcoming hypoxia limitations. However, the issues of how to improve the stability and delivery efficiency of TSAs still need to be addressed urgently. Herein, polyethylene glycol-folic acid (PEG-FA)-modified and indocyanine green (ICG)-encapsulated nanoscale Zn2+ and 2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) coordinated nanomaterials (IANM-PEG-FA) were developed as a nanobomb for targeted photothermal/thermodynamic/ion-interference cancer therapy. Co-triggered by a single 808 nm laser and mildly acidic tumor microenvironment, the photothermal agent of ICG would induce rapid decomposition of AIPH to generate alkyl radicals and release ICG and Zn2+, resulting in effectively cascaded oxygen-independent photothermal/thermodynamic therapy and co-enhanced synergistic intracellular overload of Zn2+ interference. Additionally, PEG-FA enabled favorable stability and active targeting ability to achieve low side effects and efficient tumor enrichment for good photothermal/near-infrared fluorescence imaging-guided precise tumor therapy. Significantly, the IANM-PEG-FA nanosystem exhibited remarkable anticancer effects even at low doses in hypoxic breast cancer, achieving 80% tumor elimination. Our study might provide a highly effective strategy for developing a multifunctional carrier-free nanosystem with high performance in hypoxic cancer to meet the requirements in the clinic.

Regio-isomers are utilized to design innovative AIE luminogens (AIEgens) by regulating molecular aggregation behavior. However, relevant examples are limited, and the underlying mechanism is not fully understood. Herein, a regio-isomer strategy is used to develop AIEgens by precisely regulating the intermolecular interactions in the solid state. Among the regio-isomers it is investigated, ortho- isomer (DCM-O3-O7) exhibits enhanced AIE-activity than the para- isomer (DCM-P6), and the size of the ortho- substituents is crucial for the AIE performance. The underlying mechanism of the strategy is revealed using DFT calculations and single-crystal analysis. Dual hydrogen bonds (C─H∙∙∙π and C─H∙∙∙N) are generated between the molecules, which contributes to form dimers, tetramers, and 1D supramolecular structures in the crystal. By restricting intramolecular motion and attenuating π-π interactions, solid-state fluorescence is significantly enhanced. This strategy's effectiveness is validated using other donor-acceptor fluorophores, with DCM-O6 and its analogues serving as efficient probes for bioimaging applications. Notably, DCM-OM, which bears a morpholinyl instead of piperidinyl group, displayed strong lysosome-targeting ability and photostability; DCM-OP, incorporated by the hydrophilic quaternary ammonium group, exhibited wash-free imaging and cell membrane-targeting capabilities; and DCM-O6 nanoparticles enabled high-fidelity in vivo tumor imaging. Therefore, this strategy affords a general method for designing bright AIEgens.

Photodynamic therapy (PDT) has attracted widespread attention from researchers as an emerging cancer treatment method. There have been many reports on various types of NIR-II photosensitizers for imaging and treatment of tumor sites. However, there are few reports on the development of NIR-II organic small molecule photosensitizers that have intelligent response to the tumor microenvironment, precise imaging, real-time treatment, and high biocompatibility. In this work, we developed a series of NIR-II photosensitizers (RBTs) with near-infrared excitation, good photostability, and large Stokes shift. Among them, RBT-Br exhibited higher reactive oxygen species (ROS) generation efficiency due to the introduction of halogen heavy atoms to enhance intersystem crossing (ISC). It is noteworthy that RBT-Br can generate singlet oxygen (1O2) and superoxide anion radicals (•O2-) simultaneously under 730 nm laser. Subsequently, we used molecular engineering technology to construct three pH-responsive NIR-II photosensitizers (RBT-pHs) by utilizing the closure of the lactam ring, among which RBT-pH-1 (pKa = 6.78) is able to be directionally activated under the stimulation of tumor micro-acid environment, with its fluorescence emission window reaching 933 nm. Subsequently, RBT-pH-1 NPs encapsulated in DSPE-mPEG5k were applied for PDT treatment of mouse tumors. The results showed that RBT-pH-1 NPs were activated by the acidic tumor microenvironment and generated ROS under laser excitation, exhibiting precise tumor imaging and significant tumor growth inhibition. We look forward to these multifunctional NIR-II organic small molecule photosensitizers providing a more efficient approach for clinical treatment of tumors. STATEMENT OF SIGNIFICANCE: A reversible pH-switchable NIR-II nano-photosensitizer RBT-pH-1 NPs (pKa = 6.76) is developed for precise imaging and PDT therapy of mouse tumors, which can be effectively used for targeted enrichment and activation of tumor micro-acid environments. The results show that this NIR-II photosensitizer generates ROS through tumor micro-acid environment stimulation and laser triggering, showing precise tumor imaging guidance and significant tumor growth inhibition.

Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔES-T) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. STATEMENT OF SIGNIFICANCE: (1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT); (2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells; (3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.

Aggregation-induced emission (AIE) is a unique phenomenon observed in various materials such as organic luminophores, carbon dots (CDs), organic-inorganic nanocomposites, fluorescent dye molecules, and nanoparticles (NPs). These AIE-active materials, or AIEgens, are ideal for balancing multifunctional phototheranostics and energy dissipation. AIE properties can manifest in organic fluorescent probes, rendering them effective for cancer treatment due to their ability to penetrate deeply and provide high therapeutic efficacy. This efficacy is attributed to their high photobleaching thresholds, ability to induce Stokes shifts, and capacity to activate fluorophores. Therefore, the development of innovative AIE-based materials for disease diagnosis and treatment, particularly for cancer, is both important and promising. Recent years have seen successful demonstrations of nanoparticles with AIE properties being used for photodynamic therapy (PDT) and multimodal imaging of tumor cells. These fluorophores have been shown to impact mitochondria and lysosomes, generate reactive oxygen species (ROS), activate the immune system, load and release drugs, and ultimately induce apoptosis in tumor cells. In this review, we examine previous studies on the manufacturing methods and effects of AIEgens on cancer cells, with a theranostic strategy of simultaneous treatment and imaging. We also investigate the factors affecting drug delivery on different cancer cells, including internal stimuli such as pH, ROS, enzymes, and external stimuli like near-infrared (NIR) light and ultrasound waves.

Photodynamic therapy (PDT) continues to encounter multifarious hurdles, stemming from the ineffectual preservation and delivery system of photosensitizers, the dearth of imaging navigation, and the antioxidant/hypoxic tumor microenvironment. Herein, a versatile cryomicroneedle patch (denoted as CMN-CCPH) is developed for traceable PDT. The therapeutic efficacy is further amplified by catalase (CAT)-induced oxygen (O2) generation and Cu2+-mediated glutathione (GSH) depletion. The CMN-CCPH is composed of cryomicroneedle (CMN) as the vehicle and CAT-biomineralized copper phosphate nanoflowers (CCP NFs) loaded with hematoporphyrin monomethyl ether (HMME) as the payload. Importantly, the bioactive function of HMME and CAT can be optimally maintained under the protection of CCPH and CMN for a duration surpassing 60 days, leading to bolstered bioavailability and notable enhancements in PDT efficacy. The in vivo visualization of HMME and oxyhemoglobin saturation (sO2) monitored by fluorescence (FL)/photoacoustic (PA) duplex real-time imaging unveils the noteworthy implications of CMN-delivered CCPH for intratumoral enrichment of HMME and O2 with reduced systemic toxicity. This versatile CMN patch demonstrates distinct effectiveness in neoplasm elimination, underscoring its promising clinical prospects.

NIR-II fluorescent photosensitizers as phototheranostic agents hold considerable promise in the application of mild photothermal therapy (MPTT) for tumors, as the reactive oxygen species generated during photodynamic therapy can effectively disrupt heat shock proteins. Nevertheless, the exclusive utilization of these photosensitizers to significantly augment the MPTT efficacy has rarely been substantiated, primarily due to their insufficient photodynamic performance. Herein, the utilization of high-performance NIR-II fluorescent type I/II photosensitizer (AS21:4) is presented as a simple but effective nanoplatform derived from molecule AS2 to enhance the MPTT efficacy of tumors without any additional therapeutic components. By taking advantage of heavy atom effect, AS21:4 as a type I/II photosensitizer demonstrates superior efficacy in producing 1O2 (1O2 quantum yield = 12.4%) and O2 •- among currently available NIR-II fluorescent photosensitizers with absorption exceeding 800 nm. In vitro and in vivo findings demonstrate that the 1O2 and O2 •- generated from AS21:4 induce a substantial reduction in the expression of HSP90, thereby improving the MPTT efficacy. The remarkable phototheranostic performance, substantial tumor accumulation, and prolonged tumor retention of AS21:4, establish it as a simple but superior phototheranostic agent for NIR-II fluorescence imaging-guided MPTT of tumors.

Photodynamic therapy (PDT) as an emerging therapeutic method has drawn much attention in the treatment field for cancer. Photosensitizer, which can convert photon energy into cytotoxic species under light irradiation, is the core component in PDT. The design of photosensitizers still faces problems of light absorption, targeting, penetration and oxygen dependence. With the rapid progress of material science, various photosensitizers have been developed to produce cytotoxic species for treatment of tumor with high selectivity, safety, and noninvasiveness. Besides, the applications of photosensitizers have been expanded to diverse cancer treatments such as drug release, optogenetics and immune checkpoint blockade. In this review, we summarize the recent advances of photosensitizers in various therapeutic methods for cancer. Prevailing challenges and further prospects associated with photosensitizers are also discussed.

A small molecule-based NIR-II type-I photosensitizer (IT-IC) with a strong push-pull effect and good planar π-conjugated structure was synthesized. The IT-IC NPs exhibited strong light absorption, outstanding NIR-II fluorescence emission, excellent photothermal conversion and efficient type-I/II ROS generation, showing encouraging therapeutic outcomes for hypoxic tumors.

The construction and optimization of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy (PDT), and photothermal therapy (PTT) functions remain challenging. In this study, we aimed to design and synthesize four donor-acceptor (D-A) type aggregation-induced emission molecules: PSI, TPSI, PSSI, and TPSSI. We employed phenothiazine as an electron donor and 1,3-bis(dicyanomethylidene)indan as a strong electron acceptor in the synthesis process. Among them, TPSSI exhibited efficient type I reactive oxygen species generation, high photothermal conversion efficiency (45.44 %), and near-infrared emission. These observations can be attributed to the introduction of a triphenylamine electron donor group and a thiophene unit, which resulted in increased D-A strengths, a reduced singlet-triplet energy gap, and increased free intramolecular motion. TPSSI was loaded into bovine serum albumin to prepare biocompatible TPSSI nanoparticles (NPs). Our results have indicated that TPSSI NPs can target lipid droplets with negligible dark toxicity and can efficiently generate O2•- in hypoxic tumor environments. Moreover, TPSSI NPs selectively targeted 4T1 tumor tissues and exhibited a good PDT-PTT synergistic effect in vitro and in vivo. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technologies. STATEMENT OF SIGNIFICANCE: The construction of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy, and photothermal therapy functions, and its optimization remain challenging. In this study, we construct four donor-acceptor aggregation-induced emission molecules using phenothiazine as an electron donor and 1,3-Bis(dicyanomethylidene)indan as a strong electron acceptor. By optimizing the molecular structure, an integrated phototherapy agent with fluorescence imaging ability and high photodynamic / photothermal therapy performance was prepared. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technology.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

Photodynamic therapy (PDT) is a promising cancer treatment but has limitations due to its dependence on oxygen and high-power-density photoexcitation. Here, we report polymer-based organic photosensitizers (PSs) through rational PS skeleton design and precise side-chain engineering to generate •O2- and •OH under oxygen-free conditions using ultralow-power 808 nm photoexcitation for tumor-specific photodynamic ablation. The designed organic PS skeletons can generate electron-hole pairs to sensitize H2O into •O2- and •OH under oxygen-free conditions with 808 nm photoexcitation, achieving NIR-photoexcited and oxygen-independent •O2- and •OH production. Further, compared with commonly used alkyl side chains, glycol oligomer as the PS side chain mitigates electron-hole recombination and offers more H2O molecules around the electron-hole pairs generated from the hydrophobic PS skeletons, which can yield 4-fold stronger •O2- and •OH production, thus allowing an ultralow-power photoexcitation to yield high PDT effect. Finally, the feasibility of developing activatable PSs for tumor-specific photodynamic therapy in female mice is further demonstrated under 808 nm irradiation with an ultralow-power of 15 mW cm-2. The study not only provides further insights into the PDT mechanism but also offers a general design guideline to develop an oxygen-independent organic PS using ultralow-power NIR photoexcitation for tumor-specific PDT.

Platinum supramolecular complexes based on photosensitizers have garnered great interest in photodynamic therapy (PDT) due to Pt (II) centers as chemotherapeutic agents to eliminate tumor cells completely, which greatly improve the antitumor efficacy of PDT. However, in comparison to precursor photosensitizer ligand, the formed platinum supramolecular complexes typically exhibit inferior outcomes in terms of reactive oxygen species (ROS) generation. How to boost ROS generation in the formed platinum supramolecular complexes for enhanced PDT is an enticing yet highly challenging task. Here we report a Pt-coordination-based dimeric photosensitizer complex (Cz-BTZ-Py)2Pt(OTf)2. It is found that comparing with photosensitizer ligand Cz-BTZ-Py, the formed supramolecular complex exhibit redshifts of absorption wavelength as well as enhanced ROS generation efficiency. Moreover, type-I ROS generation (O2⋅-) is produced in the formed platinum supramolecular complexes mainly due to a reduced energy gap ΔEST resulting from exciton coupling between two photosensitizer ligands. And type-I ROS (O2⋅-) generation significantly amplifies the photodynamic therapy (PDT) outcomes. In vitro evaluation shows excellent photochemotherapy performance of (Cz-BTZ-Py)2Pt(OTf)2 nanoparticles. We anticipate this work would provide a novel approach to design type-I photosensitizers for efficient PDT.

Most aggregation-induced emission (AIE) luminogens exhibit high brightness, excellent photostability, and good biocompatibility, but these AIE-active agents, which kill two birds with one stone to result in applications in both stimulated emission depletion (STED) super-resolution imaging and photodynamic therapy (PDT), have not been reported yet but are urgently needed. To meet the requirements of STED nanoscopy and PDT, D-A-π-A-D type DTPABT-HP is designed by tuning conjugated π spacers. It exhibits red-shifted emission, high PLQY of 32.04%, and impressive 1O2 generation (9.24 fold compared to RB) in nanoparticles (NPs). Then, DTPABT-HP NPs are applied in cell imaging via STED nanoscopy, especially visualizing the dynamic changes of lysosomes in the PDT process at ultrahigh resolution. After that, in vivo PDT was also conducted by DTPABT-HP NPs, resulting in significantly inhibited tumor growth, with an inhibition rate of 86%. The work here is beneficial to the design of multifunctional agents and the deep understanding of their phototheranostic mechanism in biological research.

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.

Photothermal therapy (PTT) is an effective cancer treatment method. Due to its easy focusing and tunability of the irradiation light, direct and accurate local treatment can be performed in a noninvasive manner by PTT. This treatment strategy requires the use of photothermal agents to convert light energy into heat energy, thereby achieving local heating and triggering biochemical processes to kill tumor cells. As a key factor in PTT, the photothermal conversion ability of photothermal agents directly determines the efficacy of PTT. In addition, photothermal agents generally have photothermal imaging (PTI) and photoacoustic imaging (PAI) functions, which can not only guide the optimization of irradiation conditions but also achieve the integration of disease diagnosis. If the photothermal agents have function of fluorescence imaging (FLI) or fluorescence enhancement, they can not only further improve the accuracy in disease diagnosis but also accurately determine the tumor location through multimodal imaging for corresponding treatment. In this paper, we summarize recent advances in photothermal agents with FLI or fluorescence enhancement functions for PTT and tumor diagnosis. According to the different recognition sites, the application of specific targeting photothermal agents is introduced. Finally, limitations and challenges of photothermal agents with fluorescence imaging/enhancement in the field of PTT and tumor diagnosis are prospected.

Small-molecule dyes for fluorescence imaging in the second near-infrared region (NIR-II, 900-1880 nm) hold great promise in clinical applications. Constructing donor-acceptor-donor (D-A-D) architectures has been recognized to be a feasible strategy to achieve NIR-II fluorescence. However, the development of NIR-II dyes via such a scheme is hampered by the lack of high-performance electron acceptors and donors. Diketopyrrolopyrrole (DPP), as a classic organic optoelectronic material, enjoys strong light absorption, high fluorescence quantum yield (QY), and facile derivatization. Nevertheless, its application in the NIR-II imaging field has been hindered by its limited electron-withdrawing ability and the aggregation-caused quenching (ACQ) effect resulting from the planar structure of DPP. Herein, with DPP as an electron acceptor and through donor engineering, we have successfully designed and synthesized a DPP-based dye named T-27, in which the strong D-A interaction confers excellent NIR absorption and high-brightness NIR-II fluorescence tail emission. By strategically introducing long alkyl chains on the donor unit to increase intermolecular spacing and reduce the influence of solvent molecules, T-27 exhibits an improved anti-ACQ effect in aqueous solutions. After being encapsulated into DSPE-PEG2000, T-27 nanoparticles (NPs) show a relative NIR-II fluorescence QY of 3.4% in water, representing the highest value among the DPP-based NIR-II dyes reported to date. The outstanding photophysical properties of T-27 NPs enable multimode NIR-IIa bioimaging under 808 nm excitation. As such, the T-27 NPs can distinguish mouse femoral vein and artery and achieve cerebral vascular microscopic imaging with a penetrating depth of 800 μm, demonstrating the capability for high-resolution deep-tissue imaging. This work holds significant potential in the field of bioimaging and provides a new strategy for developing bright NIR-II dyes.

Photothermal agents (PTAs) based on donor (D)-acceptor (A) NIR fluorophores show great promise in photothermal therapy due to their accessible molecular engineering to mediate excitation energy for high photothermal conversion. Except for molecular structural modification of D-A fluorophores, intermolecular arrangement in space greatly influences their excitation energy dissipation as well. But how to mediate their intermolecular arrangement is still challenging. Here we control the intermolecular orientation of chromophores via metal coordination to form Pt-bridged dimeric D-A fluorophores with different geometries. The formed configuration isomers show different intermolecular exciton coupling behaviors involving charge transfer (CT) evolution and internally limited molecular rotation, which greatly affect excited-energy dissipation. Compared with folded configuration with intense NIR emission (quantum yields (QYs) = 15.62 %), linear configuration favors non-radiative decays with low QYs (6.99 %) but enhanced photothermal conversion efficiency (PCE = 41.57 %). The self-assembled nanoparticles combining Pt-bridged dimeric D-A fluorophores with DSPE-PEG2000-RGD reveal superior photothermal therapeutic features with desirable biosafety. This research provides a new designing concept to mediate excited-state energy dissipation pathways at a sub-nano level for enhanced photothermal conversion. STATEMENT OF SIGNIFICANCE: D-A fluorophores as photothermal agents attract great attention in photothermal therapy due to their accessible molecular engineering. Besides molecular engineering of D-A fluorophores, the intermolecular packing manner is proven to greatly affect their excitation energy dissipation. But how to control intermolecular arrangement is still challenging. Here we control the intermolecular orientation of chromophores via metal coordination to form Pt-bridged dimeric D-A fluorophores with different geometries. Compared to the folded configuration, linear configuration facilitates charge transfer (CT) evolution and molecular rotation, which promotes non-radiative decays of excited energy for enhanced photothermal therapy.

The combination of multiple imaging methods has made an indelible contribution to the diagnosis, surgical navigation, treatment, and prognostic evaluation of various diseases. Due to the unique advantages of luminogens with aggregation-induced emission (AIE), their progress has been significant in the field of organic fluorescent contrast agents. Herein, this manuscript summarizes the recent advancements in AIE molecules as contrast agents for optical image-based dual/multi-modal imaging. We particularly focus on the exceptional properties of each material and the corresponding application in the diagnosis and treatment of diseases.

In the past 5 years, aggregation-induced emission luminogens (AIEgens) with emission in the second near-infrared (NIR-II) optical window have aroused great interest in bioimaging and disease phototheranostics, benefiting from the merits of deep penetration depth, reduced light scatting, high spatial resolution, and minimal photodamage. To construct NIR-II AIEgens, thiophene derivatives are frequently adopted as π-bridge by virtue of their electron-rich feature and good modifiability. Herein, we summarize the recent progress of NIR-II AIEgens by employing thiophene derivatives as π-bridge mainly compassing unsubstituted thiophene, alkyl thiophene, 3,4-ethylenedioxythiophene, and benzo[c]thiophene, with a discussion on their structure-property relationships and biomedical applications. Finally, a brief conclusion and perspective on this fascinating area are offered.

Near-infrared (NIR) fluorescence imaging-guided photodynamic therapy (PDT) technology plays an important role in treating various diseases and still attracts increasing research interests for developing novel photosensitizers (PSs) with outstanding performances. Conventional PSs such as porphyrin and rhodamine derivatives have easy self-aggregation properties in the physiological environment due to their inherent hydrophobic nature caused by their rigid molecular structure that induces strong intermolecular stacking π-π interaction, leading to serious fluorescence quenching and cytotoxic reactive oxygen species (ROS) reduction. Meanwhile, hypoxia is an inherent barrier in the microenvironment of solid tumors, seriously restricting the therapeutic outcome of conventional PDT. Aforementioned disadvantages should be overcome urgently to enhance the therapeutic effect of PSs. Novel NIR fluorescence-guided type I PSs with aggregation-induced emission (AIE), which features the advantages of improving fluorescent intensity and ROS generation efficiency at aggregation as well as outstanding oxygen tolerance, bring hope for resolving aforementioned problems simultaneously. At present, plenty of research works fully demonstrates the advancement of AIE-active PDT based on type I PSs. In this review, cutting-edge advances focusing on AIE-active NIR type I PSs that include the aspects of the photochemical mechanism of type I ROS generation, various molecular structures of reported type I PSs with NIR fluorescence and their design strategies, and typical anticancer applications are summarized. Finally, a brief conclusion is obtained, and the underlying challenges and prospects of AIE-active type I PSs are proposed.

The dense extracellular matrix (ECM) in the pancreatic cancer severely hampers the penetration of nanodrugs, which causes inferior therapeutic efficacy. To address this issue, a multifunctional liposome, namely, Lip-DTI/NO, integrating a type-I photosensitizer DTITBT with glutathione (GSH) or heat-responsive nitric oxide (NO) donor S-nitroso-N-acetyl-D-penicillamine (SNAP) is constructed to deplete the tumor ECM, leading to enhanced drug delivery and consequently improved phototherapy. The loaded DTITBT possesses multiple functions including NIR-II fluorescence imaging, efficient superoxide radical (O2 •- ) generation and excellent photothermal conversion efficiency, making it feasible for precisely pinpointing the tumor in the phototherapy process. Responding to the intracellular overexpressed glutathione or heat produced by photothermal effect of DTITBT, NO can be released from SNAP. Upon 808 nm laser irradiation, Lip-DTI/NO could selectively induce in situ generation of peroxynitrite anion (ONOO- ) in tumor after cascade processes including O2 •- production, GSH or heat-triggered NO release, and rapid reaction between O2 •- and NO. The generated ONOO- could activate the expression of endogenous matrix metalloproteinases which could efficiently digest collagen of tumor ECM, thus facilitating enhanced penetration and accumulation of Lip-DTI/NO in tumor. In vivo evaluation demonstrates the notable therapeutic efficacy via ONOO- -potentiated synergistic photodynamic-photothermal therapies on both subcutaneous and orthotopic pancreatic cancer model.

Designing mitochondria-targeting phototheranostic agents (PTAs), which can simultaneously possess exceptional and balanced type-I photodynamic therapy (PDT) and photothermal therapy (PTT) performance, still remains challenging. Herein, benzene, furan, and thiophene were utilized as π bridges to develop multifunctional PTAs. STB with thiophene as a π bridge, in particular, benefiting from stronger donor-accepter (D-A) interactions, reduced the singlet-triplet energy gap (ΔES1-T1), allowed more free intramolecular rotation, and exhibited outstanding near-infrared (NIR) emission, effective type-I reactive oxygen species (ROS) generation, and relatively high photothermal conversion efficiency (PCE) of 51.9%. In vitro and in vivo experiments demonstrated that positive-charged STB not only can actively target the mitochondria of tumor cells but also displayed strong antitumor effects and excellent in vivo imaging ability. This work subtly established a win-win strategy by π bridge engineering, breaking the barrier of making a balance between ROS generation and photothermal conversion, boosting a dual enhancement of PDT and PTT performance, and stimulating the development of multimodal imaging-guided precise cancer phototherapy.

Phototherapy (including photothermal therapy, PTT; and photodynamic therapy, PDT) has been widely used for cancer treatment, but conventional PTT/PDT show limited therapeutic effects due to the lack of disease recognition ability. The integration of fluorescence imaging with PTT/PDT can reveal tumor locations in a real-time manner, holding great potential in early diagnosis and precision treatment of cancers. However, the traditional fluorescence imaging in the visible and near-infrared-I regions (VIS/NIR-I, 400-900 nm) might be interfered by the scattering and autofluorescence from tissues, leading to a low imaging resolution and high false positive rate. The deeper near-infrared-II (NIR-II, 1000-1700 nm) fluorescence imaging can address these interferences. Combining NIR-II fluorescence imaging with PTT/PDT can significantly improve the accuracy of tumor theranostics and minimize damages to normal tissues. This review summarized recent advances in tumor PTT/PDT and NIR-II fluorophores, especially discussed achievements, challenges and prospects around NIR-II fluorescence imaging-guided PTT/PDT for cancers.

Cancer ranks as a leading threat to human life and health. Compared to conventional cancer treatments, phototheranostics shares the advantages of integrated diagnosis and therapy, outstanding therapeutic performance and good controllability. Amid diverse phototheranostic agents, small organic luminogens with aggregation-induced emission (AIEgen) tendency show predominant advantages in terms of superior photostability, large Stokes shifts, and boosted theranostic capacity as aggregates. In the past two decades, AIE-active materials have demonstrated formidable applications in disease theranostics, especially for tumors. This review mainly highlights the recent advances of orthotopic tumor phototheranostics mediated by AIEgens with a classification of different organs. Additionally, a brief discussion of current bottlenecks and future directions is outlined. We believe this review can deepen the understanding and spur more innovations on tumor theranostics by employing AIEgens. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

The infectious diseases resulting from pathogenic microbes are highly contagious and the source of infection is difficult to control, which seriously endangers life and public health safety. Although the emergence of antibiotics has a good therapeutic effect in the early stage, the massive abuse of antibiotics has brought about the evolution of pathogens with drug resistance, which has gradually weakened the lethality and availability of antibiotics. Cancer is a more serious disease than pathogenic bacteria infection, which also threatens human life and health. Traditional treatment methods have limitations such as easy recurrence, poor prognosis, many side effects, and high toxicity. These two issues have led to the exploration and development of novel therapeutic agents (such as conjugated polymers) and therapeutic strategies (such as phototherapy) to avoid the increase of drug resistance and toxic side effects. As a class of organic polymer biological functional materials with excellent photoelectric properties, Conjugated polymers (CPs) have been extensively investigated in biomedical fields, such as the detection and treatment of pathogens and tumors due to their advantages of easy modification and functionalization, good biocompatibility and low cost. A rare comprehensive overview of CPs-based detection and treatment applications has been reported. This paper reviews the design strategies and research status of CPs used in biomedicine in recent years, introduces and discusses the latest progress of their application in the detection and treatment of pathogenic microorganisms and tumors according to different detection or treatment methods, as well as the limitations and potential challenges in prospective exploration.

Light has profoundly impacted modern medicine and healthcare, with numerous luminescent agents and imaging techniques currently being used to assess health and treat diseases. As an emerging concept in luminescence, aggregation-induced emission (AIE) has shown great potential in biological applications due to its advantages in terms of brightness, biocompatibility, photostability, and positive correlation with concentration. This review provides a comprehensive summary of AIE luminogens applied in imaging of biological structure and dynamic physiological processes, disease diagnosis and treatment, and detection and monitoring of specific analytes, followed by representative works. Discussions on critical issues and perspectives on future directions are also included. This review aims to stimulate the interest of researchers from different fields, including chemistry, biology, materials science, medicine, etc., thus promoting the development of AIE in the fields of life and health.