A lipid droplet-targeted AIE photosensitizer for efficient multi-type ROS generation and breast cancer photodynamic therapy.

A mitochondria targeting aggregation-induced emission phototheranostic agent for photodynamic synergistic therapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by poor prognosis and high mortality. However, current treatment options remain inadequate, necessitating the urgent development of novel, more effective therapeutic strategies. Here, we utilize amphiphilic DSPE-PEG2000 as a scaffold to co-assemble an anionic π+ self-assembled emission-inducing emitter (photosensitizer, TMP) and an immunostimulant, CpG, via electrostatic adsorption, constructing an effective phototherapeutic diagnostic agent (termed DTC NPs). Notably, the innovatively designed TMP exhibits highly efficient aggregation-induced emission (AIE) properties, mitochondrial targeting capability, effective ROS generation, and low cytotoxicity. Upon 480 nm light irradiation, TMP induces immunogenic cell death (ICD) in tumor cells by generating abundant reactive oxygen species (ROS), thereby enabling photodynamic therapy (PDT). Crucially, intratumoral CpG enrichment stimulates immune factor production, synergistically enhancing ICD effects, promoting dendritic cell (DC) maturation, and facilitating T-cell infiltration. In vivo animal studies demonstrate that the synergistic combination of TMP's PDT activity and CpG's immunotherapeutic effects significantly suppresses tumor growth. Compared to high-dose chemotherapy, it induces more potent immune stimulation and superior therapeutic outcomes against tumors. Furthermore, the combination of DTC NPs with paclitaxel (PTX) markedly enhances therapeutic efficacy. This work represents a promising adjuvant chemotherapy strategy capable of boosting immune activation and therapeutic outcomes against drug-resistant tumors.

Construction of mannosylated glycol-nanoparticles for near-infrared bioimaging and photodynamic therapy targeting breast cancer cells

Photodynamic therapy (PDT) offers a promising approach for cancer treatment, but developing photosensitizers (PSs) with tumor targeting and near-infrared (NIR) imaging capabilities remains challenging. Herein, we designed two donor–π–acceptor (D–π–A) type photosensitizers, TC1 and TC2, by bridging electron-rich carbazole with electron-withdrawing tricyanofuran (TCF) via thiophene or EDOT moieties. Both PSs exhibited broad absorption, NIR fluorescence emission (>650 nm), and efficient type-I/II reactive oxygen species (ROS) generation under light irradiation. To improve aqueous dispersibility and breast cancer targeting, we conjugated PEGylated mannose to TC1 and TC2, yielding glycol-nanoparticles TC1M and TC2M. These nanoparticles maintained desirable NIR optical properties and ROS generation capacity while exhibiting excellent biocompatibility. Notably, mannose receptor-mediated endocytosis enabled selective uptake by MDA-MB-231 breast cancer cells over normal bEnd.3 cells, allowing targeted fluorescence imaging. Furthermore, TC2M demonstrated potent photodynamic activity, reducing cell viability to 23.15% at 20 µM under light irradiation through efficient intracellular ROS generation. This study presents mannose-functionalized glycol-nanoparticles as promising targeted theranostic agents for NIR imaging and PDT of breast cancer.

Molecular Engineering of AIE Photosensitizers for Enhanced Antitumor Phototheranostics.

Cancer remains a major threat to global public health, highlighting the urgent need for precise and effective treatment strategies. Photothermal therapy (PTT) has gained increasing attention as a promising alternative owing to its non-invasiveness, deep tissue penetration, and oxygen-independent mechanism. However, the development of high-performance organic photothermal agents (PTAs) with pronounced near-infrared absorption, high photothermal conversion efficiency (PCE), and good photostability remains challenging. Herein, we propose a synergistic strategy combining π-bridge and donor engineering to design a series of aggregation-induced emission (AIE)-active small-molecule photosensitizers. Experimental and theoretical analyses reveal that stepwise introduction of a planar thiophene π-bridge and methoxy donor groups systematically regulates the excited-state energy dissipation pathways, enabling a continuous modulation from photodynamic therapy (IsoTPA), through balanced synergistic PDT/PTT (IsoTHTPA, PCE = 57.2%), to highly efficient PTT (IsoTHTO, PCE = 64.3%), which reveals the fundamental competitive interplay between intersystem crossing and non-radiative decay. Encapsulated into nanoparticles, IsoTHTO NPs demonstrate efficient photothermal ablation of 4T1 tumor cells and significant tumor growth inhibition under 660 nm laser irradiation both in vitro and in vivo. This work presents a reasonable molecular design approach for tunable access to PDT, synergistic PDT/PTT, and PTT modalities from a single molecular platform for cancer phototheranostics.

A lysosome-targeted and polarity-responsive photosensitizer for tumor specific imaging and photodynamic therapy.

Photodynamic therapy (PDT) represents an effective and promising strategy for cancer treatment. Nevertheless, the poor targeting specificity of conventional photosensitizers has severely impeded its clinical application. Consequently, the development of novel photosensitizers that integrate imaging-guided diagnosis and synergistic phototherapeutic efficacy is highly desirable to improve PDT performance. In this work, we designed and synthesized a lysosome-targeted photosensitizer HBT-CUR with D-π-A feature based on 2-(2'-hydroxyphenyl) benzothiazole (HBT) and difluoroborate moieties for tumor image-guided PDT. HBT-CUR exhibits near-infrared (NIR) fluorescence emission, along with high polarity sensitivity, excellent stability, high lysosome-targeting specificity and good biocompatibility. By exploiting the distinct polarity differences between normal and tumor cells, HBT-CUR enables specific NIR fluorescence imaging of tumor tissues, with a fluorescence intensity ∼6-fold higher than that in normal tissues. Moreover, HBT-CUR exhibits a fast in vivo response (10 min) and prolonged duration (6 h with robust fluorescence emission). More importantly, HBT-CUR can efficiently generate singlet oxygen under light irradiation (ΦΔ = 0.70 in dioxane), thereby achieving effective photodynamic tumor ablation in MCF-7 tumor-bearing mouse models. Density functional theory (DFT) calculations reveal that the synergistic interplay between excited-state intramolecular proton transfer (ESIPT) and intramolecular charge transfer (ICT) processes contributes to the superior luminescence performance of HBT-CUR. This work presents a promising phototheranostic agent for tumor-specific image-guided photodynamic therapy, offering a new strategy for the rational design and development of tumor PDT systems.

New strategies to enhance photodynamic therapy for solid tumors

Cascade-Amplifying Immunophototherapy Nanoplatform Integrating Cocktail Drug Delivery.

Photodynamic therapy (PDT) offers the advantages of non-invasiveness, non-drug resistance, and high selectivity. However, its efficacy against melanoma is substantially limited by tumor hypoxia, elevated glutathione levels, and the strong antioxidant and light-absorbing properties of melanin. Herein, we developed a cascade-amplified biomimetic nanoplatform (Cyan-Cu) by assembling cyanobacteria (Cyan) and DSPE-PEG-NH2-decorated copper (II) phthalocyanine (CuPc) for enhanced melanoma therapy. Under 635 nm laser irradiation, the Cyan-Cu not only simultaneously generates both reactive oxygen species and heat for immunophototherapy, but also functions as a cocktail drug delivery system. In contrast to conventional microalgae used merely as photosynthetic oxygen generator or delivery vector, the Cyan effectively suppresses tyrosinase activity, thereby limiting the synthesis of antioxidant melanin and significantly potentiating both PDT and cuproptosis. Notably, the photothermal effect cascades to trigger Cyan disintegration into small cytotoxic fragments, enabling deeper tumor penetration for amplified anti-tumor efficacy. In vivo studies demonstrated that the Cyan-Cu platform reduced intratumoral melanin content while suppressing bilateral tumor growth via dual-mode immune activation. This work underscores the pivotal role of Cyan in antimelanoma therapy and illustrates the therapeutic potential of the Cyan-Cu platform as a multimodal synergistic strategy.