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The traditional design strategy for constructing highly bright solid‐state luminescent materials relies on incorporating aggregation‐induced emission (AIE) scaffolds, molecular rotors, or bulky substituents to prevent close cofacial packing, which limits the strategy diversity in developing new materials. Herein, a strategy of tuning molecular packing by twisting molecular structure of conventional aggregation‐caused quenching fluorophore is proposed to endow materials with AIE effect and enhance the solid‐state fluorescence. Accordingly, a series of 1,4‐bis(diphenylamino)‐2,5‐disubstituted benzene fluorophores exhibiting AIE characteristics, high solid‐state fluorescence efficiency (up to 0.99), wide emission color tunability, and good near‐infrared (NIR) two‐photon absorption is facilely developed. All these luminogens can specifically stain intracellular lipid droplets with a high signal‐to‐noise ratio, high biocompatibility, and good photostability. Besides, the luminogens exhibit effective reactive oxygen species (ROS) generation capability upon low‐power white light irradiation. Among them, the AIE luminogen, named BDBDC, integrating the NIR emission, good NIR two‐photon absorption and strongest ROS generation demonstrates superior performances in two‐photon fluorescence imaging of various tissues and photodynamic cancer therapy. This molecular design philosophy provides a new way of designing highly bright solid‐state fluorophores for practical applications. [ABSTRACT FROM AUTHOR]

Commercial photosensitizers (PSs) present great potential in the field of clinical photodynamic therapy (PDT) yet face a formidable challenge owing to the extremely short lifespan of singlet oxygen (1O2). Herein, the 1O2 slow‐release "platform" is proposed based on an anthracene‐groups functionalized D‐π‐A system (AIC), which can capture and slowly release 1O2 produced by commercial PSs. Meanwhile, the reversible chemical process between AIC and 1O2 is demonstrated by a series of optical experiments and high‐resolution mass spectrum. Remarkably, by virtue of 1O2 slow‐release "platform", the sustaining mitochondrial autophagy and cell apoptosis still take place when the laser is cut off with a short period of irradiation, reducing the side effect of sustained irradiation. In general, the construction of 1O2 slow‐release platform opens up exciting opportunities for improving the PDT effect of commercial PSs. [ABSTRACT FROM AUTHOR]

Engineering high‐order multiphoton excited fluorescent (H‐MPEF) materials is of significant importance for sensing, 3D optical data storage and bioimaging. However, it remains a challenging endeavor due to a lack of appropriate construction strategies. This study demonstrates that incorporating octupolar modules within metal‐organic framework (MOF) offers new possibilities for the design of highly attractive H‐MPEF materials. Constructed from a typical MOF (UiO(bpdc)), the in situ formation of multibranched octupolar cyclometallated iridium(III) modules via post‐ligand coordination modification endowed the framework with enlarged static hyperpolarizabilities, an extended conjugated system, and enhanced charge transfer, ultimately unlocking its second near‐infrared (NIR‐II, 1000–1700 nm) light activated H‐MPEF performance including three‐ and four‐photon activity. Moreover, these exciting features, combined with subsequent orotic acid‐capping, enabled its application in cancer cell‐specific targeting oncotherapy using tissue‐penetrating NIR‐II light. This finding highlights the vital role of octupoles in H‐MPEF performance and sets a benchmark for unlocking the multiphoton activity of MOFs at the molecular level for deep‐seated tumor fluorescence imaging and therapy. [ABSTRACT FROM AUTHOR]

We present a two-photon (2P, 800 nm) PDT cyclometalated Iridium(iii) complex (Ir-Es) that targets the intracellular nucleus. The complex is capable of migrating sequentially from the nucleus to mitochondria and inducing dual-damage under light exposure. This study suggests that with minor modification of the terminal moieties of complexes, their final intracellular destinations and PDT efficiency can be significantly impacted. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT), characterized by high treatment efficiency, absence of drug resistance, minimal trauma, and few side effects, has gradually emerged as a novel and alternative clinical approach compared to traditional surgical resection, chemotherapy and radiation. Whereas, considering the limited diffusion distance and short lifespan of reactive oxygen species (ROS), as well as the hypoxic tumor microenvironment, it is crucial to design photosensitizers (PSs) with suborganelle specific targeting ability and low-oxygen dependence for accurate and highly efficient photodynamic therapy. In this study, we have meticulously designed three PSs, namely CIH , CIBr , and CIPh , based on molecular engineering. Theoretical calculation demonstrate that the three compounds possess good molecular planarity with calculated S 1 -T 1 energy gaps (Δ E S1-T1) of 1.04 eV for CIH , 0.92 eV for CIBr , and 0.84 eV for CIPh respectively. Notably, CIPh showcases remarkable dual subcellular targeting capability towards lipid droplets (LDs) and mitochondria owing to the synergistic effect of lipophilicity derived from coumarin's inherent properties combined with electropositivity conferred by indole salt cations. Furthermore , CIPh demonstrates exclusive release of singlet oxygen (1O 2)and highly efficient superoxide anion free radicals(O 2 ⦁−) upon light irradiation supported by its smallest S1-T1 energy gap (Δ E S1-T1 = 0.84 eV). This leads to compromised integrity of LDs along with mitochondrial membrane potential, resulting in profound apoptosis induction in HepG2 cells. This successful example of molecular engineering guided by density functional theory (DFT) provides valuable experience for the development of more effective PSs with superior dual targeting specificity. It also provides a new idea for the development of advanced PSs with efficient and accurate ROS generation ability towards fluorescence imaging-guided hypoxic tumor therapy. [Display omitted] • CIPh realized elevated levels of O 2 ⦁− and 1O 2 "turn on". • CIPh can effectively kill cancer cells for synergetic damage on LDs and mitochondria. • Reveal the mechanism of cell death. [ABSTRACT FROM AUTHOR]

Oxygen concentration and penetration depth are the two key factors that influence the therapeutic effect of photodynamic therapy (PDT) in hypoxic tumors. Developing a simple strategy to construct advanced type I photosensitizers (PSs) with near-infrared region (NIR) absorption has a wide application prospect but remains a challenge. Herein, based on simple D-π-A conjugated CQ-SO 3 and CQ-S-SO 3 , bovine serum albumin (BSA) was elaborately selected to construct the supramolecular assemblies CQ-SO 3 @BSA and CQ-S-SO 3 @BSA. Encouragingly, the high-stability CQ-S-SO 3 @BSA exhibited superior superoxide anion (O 2 ‑• ) generation and activated three-photon fluorescence properties (1240 nm excitation). Confocal microscopy imaging indicated that CQ-S-SO 3 @BSA can specifically target cancer cell membranes and penetrate 120 µm tissue depth, triggering cancer cell apoptosis under NIR-II light irradiation even in a hypoxic environment. This discovery emphasizes the potential for "killing two birds with one stone" based on supramolecular assembly, thereby opening up new possibilities for phototherapy. • Protein co-assembled strategy. • Superior O 2 ‑• generation. • NIR-II imaging-guided antihypoxic phototherapy. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) have attracted much attention due to their unique structure and key connections with various organelles in cells. Here, we constructed a reactive oxygen species (ROS) -generating system by carefully designing photosensitizers (TT2CN) with proper lipophilicity, excellent light stability and cell imaging ability. In detail, TT2CN can selectively accumulate into LDs (as carriers for TT2CN) and then a subcellular photo-inducible ROS-generating system was formed. Confocal fluorescence imaging revealed the contact behavior of dynamic LDs with other organelles in the cells and the photo-produced ROS can induce multiple organelle damages. Flow cytometry, AM / PI and 3D multicellular tumor spheres (3D MCTs) experiments further verified and demonstrated its promising biological application. This work not only uncovers the communication behavior between LDs and other organelles, but also provides a new anticancer strategy of LDs-mediated photodynamic therapy. [Display omitted] • TT2CN has excellent photostability and cell imaging ability. • Constructing ROS-generating system, viz, TT2CN -loaded LDs. • Confocal fluorescence imaging revealed the contact behavior of this ROS-generating system with other organelles. • ROS-generating system outstanding capability to mediate multiple subcellular organelle damage. [ABSTRACT FROM AUTHOR]

An amphiphilic small-molecule PS (CMOOH) anchoring on the two original and derived suborganelles (ER and LDs) were prepared, producing ROS for causing ERS and lipophagy to accelerate the apoptosis of cancer cells, of which apoptotic mechanism was observed by CLSM/FLIM. [Display omitted] • CMOOH discriminatively visualize derivational suborganelles via FILM. • CMOOH generated ROS to cause rapid cell apoptosis via "knock-on" effect. • The ERS and lipophagy mediated apoptosis were precisely revealed for guiding PDT. The sub-organelle targeting group is generally introduced into photosensitizer (PS) to expedite cancer cell apoptosis through oxidized specifically subcellular organelle for photodynamic therapy (PDT). Nevertheless, the exploitation of PS by targeting original and derived organelles, which might utilize a "knock-on" effect to cause rapid apoptosis, is still a huge challenge. Herein, an amphiphilic small-molecule PS, named CMOOH , was constructed by lipophilic coumarin and hydrophilic hydroxyl group, which not only anchored on the two sub-organelles with a derivational relationship (endoplasmic reticulum (ER) and lipid droplets (LDs)) but also could produce reactive oxygen species (ROS) simultaneously to facilitate the apoptosis of cancer cells under the light irradiation. Encouragingly, CMOOH firstly deciphered the apoptotic mechanism mediated by endoplasmic reticulum stress (ERS) and lipophagy by confocal laser scanning microscopy (CLSM) and two-photon fluorescence lifetime imaging microscopy (FLIM), deriving from the applicable amphipathicity, fluorescent lifetime and excellent nonlinear optical property. This tactic provided an innovative platform for treatment and imaging and renewed awareness of heightening the cancer-cell apoptosis via oxidative damage of "affinal" sub-organelles. [ABSTRACT FROM AUTHOR]

Minimizing the concomitant damage to healthy tissues is the key factor to guarantee precise and efficient photodynamic therapy (PDT). Herein, a specifically cancer cell lysosome targeted pre-photosensitizer with the suitable pH-response range (pH < 5.0) has been rationally designed by simple molecular engineering and successfully applied for switch-on PDT, which is further confirmed by the single crystal structure, pH test, cell uptake, and in vivo treatments. Fluorescence imaging on mouse model evidences that it is "off" in normal tissue and "on" in tumor region. This lysosome-targeting activated pre-photosensitizer provides new opportunities in the rational design of tumor specifically responsive photosensitizer. [Display omitted] • Simple molecular engineering to realize low pH response range (pH < 5.0). • MSN can only be activated in lysosome of cancer cells with efficient single dioxygen production. • MSN is in "off" state in normal tissue and in "on" state in tumor region. • MSN acts as an efficient pre-photosensitizer for restraining tumor growth. [ABSTRACT FROM AUTHOR]

Two isomorphic theranostic agents, named 6-TDE and 7-TDE, were designed and prepared by substituent position modification, exhibiting the grid-like and wave-like structure. Specially, 7-TDE possessed favorable ROS (Type I and Type II) as well as self-monitoring mitochondrial autophagy and multimodal imaging. [Display omitted] • Two interesting packing modes, the grid-like and wave-like structure through substituent position modification on packing mode. This study provides the new insight into the "Formula-Aggergete-Property" relationship of chemical structure. • A photosensitizer capable of photodynamic therapy (Type I and Type II) and self-monitoring mitochondrial autophagy. • The photosensitizer presented outstanding performance in multimodal imaging, including fluorescence imaging (FLI), photoacoustic imaging (PAI) and photothermal imaging (PTI). Precise design of organic photosensitizers (PSs) promoted the technological innovation for multimodal imaging-guided synergistic therapy. Nonetheless, various group substitution could not only optimize the basic photophysical behavior, but possibly change the aggregate, which handicaps the deep understanding of the "Formula-Aggergete-Property" relationship. Bearing this in mind, herein two isomers, named 6-TDE and 7-TDE , were prepared via substituting position modification. Among them, 6-TDE exhibited the grid-like structure, while 7-TDE presented wavy-like structure. Despite the aggregates were different, 6-TDE and 7-TDE shared common features including partly twisted backbone and non-overlapped-orbit, hence resulting in similar optical physical behavior such as decent extinction coefficient, near-IR emission, large stockes shifts, etc. Meanwhile, though two PSs could both generated Type-I and Type-II ROS, 7-TDE possessed smaller singlet–triplet splitting (ΔE ST), which exhibited favorable ROS as well as outstanding mitochondrial targeting, achieving efficient photodynamic therapy (PDT) effect. During this process, mitochondrial autophagy could be tracked and observed effectively and in real-time. Moreover, 7-TDE presented outstanding performance in multimodal imaging, including fluorescence imaging (FLI), photoacoustic imaging (PAI) and photothermal imaging (PTI). This study enriches the strategy of precise molecular engineering to optimize theranostic agents. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) have appeared as a variety of promising nanomaterials for photodynamic therapy (PDT) owing to their excellent biosafety and structural diversity. However, finite aqueous dispersibility, deficient subcellular targeting ability and undesirable PDT efficiency had seriously restricted their biomedical application. Herein, we prepared two solution-dispersible nanoparticle COFs via a mild solution-phase synthesis, denoted as EB-TFP and DPP-TFP, investigating the effect of COF's surface charges on their subcellular targeting ability and PDT efficiency. With tuning the COF's surface charges, the positive charged COFs (EB-TFP) possessed the elevated mitochondrial targeting ability, higher O 2 -. generation ability and fluorescence at 510 nm. Therefore, EB-TFP successfully employed as multifunctional PSs with excellent mitochondrial targeting ability for the imaging-guided type Ⅰ PDT. This work provides a "killing two birds with one stone" strategy to improve subcellular targeting and ROS generation ability for expanding the biomedical applications via tuning the COFs' surface charges. • Two solution-dispersible nanoparticle COFs based probes were designed and synthesized via a mild solution-phase synthesis. • The two COFs based probes was successfully employed as multifunctional probes for the imaging-guided type Ⅰ PDT. • The effect of COF's surface charges on their subcellular targeting ability and PDT efficiency was investigated. [ABSTRACT FROM AUTHOR]

Photodynamic therapy has been generally developed and approved as a promising theranostic technique in recent years, which requires photosensitizers to bear high efficiency of reactive oxygen species production, precisely targeting ability and excellent biocompatibility. The real-time monitoring the microenvironments such as viscosity dynamic involved in mitophagy mediated by photodynamic therapy is significantly important to understand therapeutic process but barely reported. In this work, a pyridinium-functionalized triphenylamine derivative, (E)-4-(2-(4'-(diphenylamino)-[1,1′-biphenyl]-4-yl)vinyl)-1-methylpyridin-1-ium iodide (Mito-I), was exploited as photosensitizer for mitochondria-targeted photodynamic therapy and as fluorescent probe for imaging the mitochondrial viscosity dynamic during mitophagy simultaneously. The results indicated that the additional phenyl ring in Mito-I was beneficial to promote its efficiency of singlet oxygen production. The excellent capability of targeting mitochondria and singlet oxygen generation allowed Mito-I for the specifically mitochondria-targeted photodynamic therapy. Moreover, Mito-I displayed off-on fluorescence response to viscosity with high selectivity and sensitivity. The observed enhancement in fluorescence intensity of Mito-I revealed the increasingly mitochondrial viscosity during mitophagy mediated by the photodynamic therapy of Mito-I. As a result, this work presents a rare example to realize the mitochondria-targeting photodynamic therapy as well as the real-time monitoring viscosity dynamic during mitophagy, which is of great importance for the basic medical research involved in photodynamic therapy. [Display omitted] • A pyridinium-functionalized triphenylamine was exploited as photosensitizer and viscosity probe. • Its efficiency of 1O 2 production was improved by introducing an additional phenyl ring. • Mitochondria-targeted photodynamic therapy was achieved by this triphenylamine derivative. • It exhibited off-on fluorescence response to viscosity with high selectivity and sensitivity. • The real-time monitoring mitochondrial viscosity variation during mitophagy was realized simultaneously. [ABSTRACT FROM AUTHOR]

Finely tuning the hydrophobicity of pyridinium-based probes by regulating the length of the alkyl chains on pyridinium unit to achieve the precisely mitochondria-targeted photodynamic therapy and mitophagic tracking through cooperating with electrostatic interaction. • A series of pyridinium-based probes with high efficiency of ROS generation are rationally designed. • The hydrophobicity of these probes can be finely tuned by modulating the length of the alkyl chains on pyridinium unit. • The precisely mitochondrial targeting can be achieved through adjusting the hydrophobicity of these probes. • The mitochondria-targeted photodynamic therapy and mitophagy tracking can be simultaneously realized by probe TL8C. Targeting mitochondria and dynamically tracking mitophagy are profoundly important in the field of photodynamic therapy (PDT) which relies on the photosensitizers (PSs) under light irradiation. While simultaneously realizing the effective reactive oxygen species (ROS) generation, accurately mitochondrial targeting, and dynamic tracking in a single PS still is a challenging issue. In this context, a series of pyridinium-based cationic fluorogens with aggregation induced emission (AIE) has been developed for this issue. The hydrophobicity of these fluorogens can be finely tuned by modulating the length of the alkyl chains on pyridinium unit. The well-tuned hydrophobicity of TL8C with C 8 -alkyl chain gives rise to the specifically mitochondrial targeting capability of TL8C based on the appropriate synergistic effect of hydrophobic and electrostatic interaction. Meanwhile, TL8C can produce ROS in high efficiency. The excellent mitochondrial targeting and the effective ROS generation allow TL8C for the specifically mitochondria-targeted PDT as well as the real time monitoring of mitophagy. [ABSTRACT FROM AUTHOR]