Na Zhao

Lipophagy, a selective autophagic pathway, maintains lipid homeostasis and contributes to ferroptosis by supplying lipid peroxidation substrates. However, organic photosensitizers that activate lipophagy to promote ferroptosis remain scarce. Herein, we developed a NIR-II emissive photosensitizer (MBTTD) targeting lipid droplets (LDs). Compared with its analogue MBTTA, stronger electron-withdrawing groups bathochromically shifted absorption/emission and tuned excited-state decay, enabling efficient type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency. MBTTD nanoparticles (NPs) localized to LDs upon cellular uptake. Upon 808 nm laser irradiation, MBTTD NP-mediated phototherapy disrupted LDs and induced Rab7-regulated lipophagy, releasing polyunsaturated fatty acids that underwent ROS-driven peroxidation, triggering extensive lipid peroxidation and ferroptosis. Concurrently, MBTTD-NP-mediated phototherapy triggered endoplasmic reticulum stress and apoptosis. MBTTD NPs showed favorable biocompatibility and potent therapeutic efficacy in multicellular tumor spheroids. In vivo studies revealed that MBTTD NPs enabled NIR-II imaging-guided phototherapy, suppressing 4T1 tumor growth without significant systemic toxicity.

Precision phototheranostics of malignant tumors has become a prominent research focus in the field of biomedicine. However, conventional organic dyes are severely limited in their efficacy for tumor theranostics due to the aggregation-caused quenching (ACQ) effect. By precisely regulating the stacking mode, J-aggregation effectively suppresses ACQ and endows organic dyes with unique photophysical properties, including a red-shifted spectrum, an enhanced molar extinction coefficient, and improved efficiency in photothermal conversion and reactive oxygen species generation. Consequently, it has emerged as an effective strategy to advance tumor phototheranostics. Based on the exciton-coupling model, this Article elucidates the intrinsic relationship between molecular stacking modes and the theranostic performance of organic dyes. It systematically summarizes recent progress in the application of J-aggregates to tumor fluorescence/photoacoustic imaging, photothermal therapy, photodynamic therapy, and multimodal theranostics. Furthermore, current key challenges and future research directions for J-aggregated organic dyes are discussed. This Article aims to provide theoretical insights and design principles for the rational development of novel J-aggregated organic dyes and the construction of precise tumor theranostics systems, thereby facilitating further advancement and clinical translation of tumor phototheranostics.

Cancer therapeutic strategies centered on synergistic ferroptosis and cuproptosis have attracted considerable interest. However, current approaches predominantly relying on Fe and Cu sources face limitations including single mode of reactive oxygen species (ROS) production, poor organelle targeting, and lack of imaging capabilities. Herein, we developed a multifunctional nanoplatform, NMC NPs, by integrating a type I aggregation‐induced emission photosensitizer (NTI) with a Cu‐based nanozyme (MOF‐Cu). This design enables efficient ROS generation, precise mitochondria targeting, and real‐time fluorescence imaging, allowing more effective activation of ferroptosis and cuproptosis. Upon cellular uptake, MOF‐Cu framework dissociates and releases NTI, which selectively accumulates in mitochondria. Under 635 nm laser irradiation, NTI generates type I ROS, triggering lipid peroxidation and activating ferroptosis. Simultaneously, MOF‐Cu nanozyme exerts dual peroxidase‐like and glutathione peroxidase‐like activities, catalyzing H ₂ O ₂ into hydroxyl radicals while depleting glutathione and releasing Cu ⁺ ions, further promoting ferroptosis. Notably, the released Cu ⁺ ions further disrupt mitochondrial function, induce dihydrolipoamide S‐acetyltransferase aggregation, and activate cuproptosis. The synergistic action efficiently enhances immunogenic cell death. In vivo studies confirmed the potent antitumor efficacy of NMC NPs with minimal side effect. This study provides new insights into the cooperative regulation of metal‐dependent cell death and advances the design of integrated theranostic nanoplatforms.

BODIPY dyes and their analogues have attracted considerable interest due to their structural diversity and functional versatility, holding significant importance in fields such as materials science, catalytic chemistry, and biomedicine. Studies have shown that the introduction of weakly covalent bonds and phenyl rotors into boron‐based scaffold can effectively twist the conjugated system, thereby imparting aggregation‐induced emission (AIE) characteristics. This strategy successfully addresses the issue of aggregation‐caused quenching commonly associated with the planar and rigid conjugated structures of conventional BODIPY dyes and their analogues. As a result, AIE‐active BODIPY dyes and their analogues exhibit higher sensitivity and superior fluorescence performance compared to traditional materials, broadening their applicability in bioimaging and phototherapeutic cancer treatment. This review summarizes recent advances in the biomedical applications of AIE‐active BODIPY dyes and their analogues, with a particular focus on organelle‐targeted imaging including lipid droplets, lysosomes, and mitochondria, as well as cancer phototherapies such as photodynamic and photothermal therapy (PDT and PTT). Finally, we discuss current challenges and limitations in the field and propose promising research directions to inspire future innovations for improving disease diagnosis and treatment efficacy, as well as for developing minimally invasive therapeutic strategies.

Lipid droplets (LDs) play critical roles in regulating key physiological processes. LD-targeted phototherapy is a promising strategy for precision cancer therapy due to its capacity to induce distinct programmed cell death pathways.

An NIR-II type I photosensitizer with an aggregation-induced emission effect was developed to selectively stain the endoplasmic reticulum, which further triggered pyroptotic cell death under 635 nm laser irradiation.