Phototherapy includes photodynamic therapy (PDT) and photothermal therapy (PTT). Compared with surgical resection, chemotherapy, and radiotherapy, phototherapy has gained considerable attention for cancer treatment owing to advantages such as light controllability, safety, noninvasiveness, and high efficiency [1]. Presently, PDT is mainly based on the type II mechanism, which is highly oxygen-dependent and involves the production of singlet oxygen (1O2) to kill cancer cells; however, the severe hypoxic environment in solid tumors limits the use of PDT [2], [3], [4], [5], [6], [7], [8]. In contrast, type I PDT has a low oxygen dependence and can produce highly cytotoxic superoxide free radicals (O2•−) and hydroxyl free radicals (•OH) even in the case of severe oxygen deficiency (1% O2), thereby effectively killing tumor cells [9], [10], [11]. PTT kills cancer cells locally by converting light energy into heat. Owing to the heat shock effect of PTT, the efficacy of PTT alone is usually unsatisfactory [12,13]. The combination of type I PDT and PTT is expected to overcome the hypoxic conditions of tumors and the heat shock effect caused by PTT, achieve efficient synergistic effects, and significantly improve antitumor performance [14], [15], [16].

Photoluminescence (PL) bioimaging technology provides a reliable basis for the diagnosis and treatment of lesions. Near-infrared PL imaging has considerable advantages, such as high sensitivity, tissue penetration, noninvasiveness, and real-time monitoring, for tracking and diagnosing diseased tissues [17]. Molecules with aggregation-induced emission (AIE) emit almost noting in solution; however, when aggregated, AIE molecules exhibit strong PL, thereby having considerable potential for in vivo tumor imaging [18,19]. Studies have indicated that AIE phototherapeutic agents exhibit enhanced reactive oxygen species (ROS) production and high photothermal effects in the aggregated state [20], [21], [22]. Additionally, studies have shown that reducing the energy gap between the lowest singlet state (S1) and lowest triplet state (T1) is effective for the construction of highly efficient type I photosensitizers [23], [24], [25], [26]. Additionally, owing to the large number of freely moving molecular rotators or vibrators in the AIE molecular structure, the balance between radiative and nonradiative decay can be adjusted by promoting or inhibiting intramolecular motion. Presently, constructing a single phototherapy agent that exhibits PL and possesses type I PDT and PTT characteristics, while also optimizing its functions, remains a challenging task. AIE photosensitizers with a donor–acceptor (D-A) structure have received extensive attention in the field of cancer diagnosis and treatment. The D-A structure can promote the separation of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), which can improve the intersystem crossing process and enhance the ability to generate ROS [27], [28], [29]. Currently, most of the reported AIE photosensitizers are mainly based on type II PDT that produces 1O2. However, their ROS production efficiency is often limited by the hypoxic conditions prevalent in tumor tissues. The development of type I photosensitizers offers a promising solution to address the efficacy limitations of type II PDT resulting from the hypoxic tumor microenvironment. To this end, in this study, we aimed to design and synthesized four new D-A type AIE photosensitizers.

The biocompatibility and tumor-targeting ability of AIE small organic molecules are not ideal and significantly affect the efficacy of phototherapy. Therefore, selecting an appropriate carrier to transport therapeutic molecules to the tumor site in the form of nanoparticles (NPs) with an appropriate particle size of 20–200 nm is necessary [30,31]. Bovine serum albumin (BSA) is a natural delivery carrier of hydrophobic molecules in vivo that can target and enrich tumor cells via endocytosis, which is mediated by albumin receptors that are highly expressed on the surface of tumor cells. In a physiological environment with a pH of 7.4, BSA is negatively charged, thereby preventing it from being taken up by the reticuloendothelial system, which prolongs its blood circulation time [32], [33], [34]. Additionally, ROS produced by photosensitizers have a short lifetime and diffusion distance, so targeting organelles can improve the efficacy of PDT [35]. Lipid droplets (LDs) are subcellular organelles that play important roles in energy storage, lipid metabolism, and signal transduction. Owing to the need for infinite proliferation, numerous LDs accumulate in cancer cells [36], [37], [38]. Therefore, the selection of appropriate delivery carriers to enhance the ability of therapeutic molecules to target tumor tissues and subcellular organelles is important for achieving accurate diagnosis and treatment of tumors.

In this study, we aimed to construct four D-A type AIE molecules using phenothiazine as a strong electron donor and 1,3-bis(dicyanomethylidene)indan as a strong electron acceptor. Phenothiazine, with a butterfly-shaped twisted structure, contains electron-rich N and S atoms that serve as strong electron donors. The thiophene units, acting as flexible rotors, can improve the electron-donating ability and expand the π-conjugated structure. A molecule PSSI with strong D-A interactions constructed by coupling phenothiazine with a strong electron acceptor through dithiophene, has fine PL, photodynamic and photothermal capabilities. The highly distorted conformation of the triphenylamine (TPA) unit acts as an electron donor and a molecular rotor. The TPA unit was introduced into PSSI to improve the donor ability and regulate the molecular spacing in the aggregation state, thereby endowing TPSSI with near-infrared absorption and emission, efficient type I ROS (O2•−) generation ability, and a good photothermal effect. Thus, the TPA and thiophene units together manipulate the energy dissipation of the three excited states. TPSSI NPs were prepared by encapsulating TPSSI with BSA, which showed an efficient phototherapy effect in NIR fluorescence imaging guided PDT-PTT combined therapy as a single-component therapeutic agent. Hence, we constructed an all-in-one phototherapy agent with fluorescence imaging capabilities and high PDT–PTT performance.