Far-red and near-infrared (NIR) fluorescent materials possessing the characteristics of strong two-photon absorption and aggregation-induced emission (AIE) as well as specific targeting capability are much-sought-after for bioimaging and therapeutic applications due to their deep penetration depth and high resolution. Herein, a series of dipolar far-red and NIR AIE luminogens with a strong push-pull effect are designed and synthesized. The obtained fluorophores display bright far-red and NIR solid-state fluorescence with a high quantum yield of up to 30%, large Stokes shifts of up to 244 nm, and large two-photon absorption cross-sections of up to 887 GM. A total of three neutral AIEgens show specific lipid droplet (LD)-targeting capability, while the one with cationic and lipophilic characteristics tends to target the mitochondria specifically. All of the molecules demonstrate good biocompatibility, high brightness, and superior photostability. They also serve as efficient two-photon fluorescence-imaging agents for the clear visualization of LDs or mitochondria in living cells and tissues with deep tissue penetration (up to 150 μm) and high contrast. These AIEgens can efficiently generate singlet oxygen upon light irradiation for the photodynamic ablation of cancer cells. All of these intriguing results prove that these far-red and NIR AIEgens are excellent candidates for the two-photon fluorescence imaging of LDs or mitochondria and organelle-targeting photodynamic cancer therapy.

Although photodynamic therapy (PDT) has thrived as a promising treatment, highly active photosensitizers (PSs) and intense light power can cause treatment overdose. However, extra therapeutic response probes make the monitoring process complicated, ex situ and delayed. Now, this challenge is addressed by a self-reporting cationic PS, named TPE-4EP+, with aggregation-induced emission characteristic. The molecule undergoes mitochondria-to-nucleus translocation during apoptosis induced by PDT, thus enabling the in situ real-time monitoring via fluorescence migration. Moreover, by molecular charge engineering, we prove that the in situ translocation of TPE-4EP+ is mainly attributed to the enhanced interaction with DNA imposed by its multivalent positive charge. The ability of PS to provide PDT with real-time diagnosis help control the treatment dose that can avoid excessive phototoxicity and minimize potential side effect. Future development of new generation of PS is envisioned.

Nonlinear optical microscopy has become a powerful tool in bioimaging research due to its unique capabilities of deep optical sectioning, high‐spatial‐resolution imaging, and 3D reconstruction of biological specimens. Developing organic fluorescent probes with strong nonlinear optical effects, in particular third‐harmonic generation (THG), is promising for exploiting nonlinear microscopic imaging for biomedical applications. Herein, a simple method for preparing organic nanocrystals based on an aggregation‐induced emission (AIE) luminogen (DCCN) with bright near‐infrared emission is successfully demonstrated. Aggregation‐induced nonlinear optical effects, including two‐photon fluorescence (2PF), three‐photon fluorescence (3PF), and THG, of DCCN are observed in nanoparticles, especially for crystalline nanoparticles. The nanocrystals of DCCN are successfully applied for 2PF microscopy at 1040 nm NIR‐II excitation and THG microscopy at 1560 nm NIR‐II excitation, respectively, to reconstruct the 3D vasculature of the mouse cerebral vasculature. Impressively, the THG microscopy provides much higher spatial resolution and brightness than the 2PF microscopy and can visualize small vessels with diameters of ≈2.7 µm at the deepest depth of 800 µm in a mouse brain. Thus, this is expected to inspire new insights into the development of advanced AIE materials with multiple nonlinearity, in particular THG, for multimodal nonlinear optical microscopy.

The development of novel photosensitizing agents with aggregation-induced emission (AIE) properties has fueled significant advances in the field of photodynamic therapy (PDT). An electroporation method was used to prepare tumorexocytosed exosome/AIE luminogen (AIEgen) hybrid nanovesicles (DES) that could facilitate efficient tumor penetration. Dexamethasone was then used to normalize vascular function within the tumor microenvironment (TME) to reduce local hypoxia, therebys ignificantly enhancing the PDT efficacy of DES nanovesicles,a nd allowing them to effectively inhibit tumor growth. The hybridization of AIEgen and biological tumor-exocytosed exosomes was achieved for the first time, and combined with PDT approaches by normalizing the intratumoral vasculature as am eans of reducing local tissue hypoxia. This work highlights anew approach to the design of AIEgen-based PDT systems and underscores the potential clinical value of AIEgens.

Mitochondria-targeted photosensitizers with highly efficient singlet oxygen generation, bright near-infrared AIE and good two-photon absorption are obtained through ingenious molecular engineering for cancer cell-selective photodynamic therapy.

A series of new isophorone derivatives (1-5), incorporating the heterocyclic ring or aza-crown-ether group, with large Stokes shifts (>140 nm), have been synthesized and characterized. 1-4 display aggregation-induced emission behaviors, while dye 5 is highly emissive in solution but quenched in the solid state. It was found that the tuning of emission color of the isophorone-based compounds in the solid state could be conveniently accomplished by changing the terminal substituent group. The photophysical properties in solution, aqueous suspension, and crystalline state, along with their relationships, are comparatively investigated. Crystallographic data of 1-4 indicate that the existence of multiple intermolecular hydrogen bonding interactions between the adjacent molecules restricts the intramolecular vibration and rotation and enables compounds 1-4 to emit intensely in the solid state. The size and growth processes of particles with different water fractions were studied using a scanning electron microscope, indicating that smaller globular nanoparticles in aqueous suspension are in favor of fluorescence emissions. The above results suggest that substituent groups have a great influence on their molecular packing, electronic structure, and aggregation-induced emission properties. In addition, fluorescence cell imaging experiment proved the potential application of 5.

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Phototheranostic agents have thrived as promising tools for cancer theranostics because of the integration of sensitive in situ fluorescence imaging and effective multi‐model synergistic therapy. However, how to manipulate the intangible photon energy transfer to balance the competitive radiative and nonradiative processes is still challenging. Although numerous phototheranostic molecules are reported, their complicated molecular design and tedious synthesis often stumble further their development. Herein, three simple molecules with electron donating−accepting structures are developed. The electron acceptor engineering on molecules by introducing acridinium unit gives rise to TPEDCAc with aggregation‐induced second near‐infrared emission (AIE NIR‐II), high reactive oxygen species generation capability, and excellent photothermal conversion efficiency (44.8%) due to the drastic intramolecular motion of large acridinium rotor and balanced AIE effect. Experimental analysis and calculation on the controlled molecules suggested that large torsional angle and the strong electron‐withdrawing ability of the acridinium unit are keys for NIR‐II emission and balanced photodynamic/photothermal conversion. Impressively, the positively charged TPEDCAc shows mitochondria‐targeting capability and high performance in in vivo multi‐modal cancer theranostics under NIR laser irradiation. Hence, this work not only provides a single NIR‐II AIE‐based multi‐modal cancer theranostic system but inspires new insights into future development of new theranostic platforms.