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Photodynamic therapy (PDT) is a promising noninvasive treatment option for patients suffering from superficial tumors, such as oral cancer. However, for photosensitizers (PSs), it remains a grand challenge to simultaneously excel in all the key performance indicators including effective singlet oxygen (1O2) generation under clinical laser, specific targeting function and stable far-red (FR)/near-infrared (NIR) emission with low dark toxicity. In addition, traditional PS nanoparticles (NPs) for clinical use suffer from quenched fluorescence and reduced 1O2 production caused by molecular aggregation. To address these issues, AIEPS5 with aggregation-induced FR/NIR emission and effective 1O2 generation under 532 nm laser irradiation is designed by precise optimization of the chemical structure. By attaching a polyethylene glycol (PEG) chain onto AIEPS5, the yielded amphiphilic AIEPS5-PEG2000 can spontaneously self-assemble into water dispersible NPs, which are further endowed with targeted delivery function via the decoration of anti-Her-2 nanobody (NB). The bespoke AIEPS5-NPs-NB exhibit effective 1O2 generation capability, bright FR/NIR emission centered at 680 nm, and negligible dark toxicity, which outperform Heimbofen, a clinically approved PS in PDT using a patient-derived tumor xenograft model.

Maximization of phototoxic damage on tumor with minimized side effect on normal tissue is essential for effective anticancer photodynamic therapy (PDT). This requires highly cancer-cell-specific or even cancer-cell-organelle-specific synthesis or delivery of efficient photosensitizers (PSs) in vitro and in vivo, which is difficult to achieve. Herein, we report a strategy of cancer-cell-activated PS synthesis, by which an efficient mitochondria-targeting photosensitizer with aggregation-induced-emission (AIE) feature can be selectively synthesized as an efficient image-guided PDT agent inside cancer cells. MOF-199, a CuII -based metal-organic framework, was selected as an inert carrier to load the PS precursors for efficient delivery and served as a CuI catalyst source for in situ click reaction to form PSs exclusively in cancer cells. The in situ synthesized PS showed mitochondria-targeting capability, allowing potent cancer-cell-specific ablation under light irradiation. The high specificity of PSs produced in cancer cells also makes it safer post-treatment.

Tumor accumulation and intratumoral singlet oxygen (1O2) generation efficiency of photosensitizers (PSs) are two essential factors that determine their photodynamic therapy (PDT) efficacies. How to maximize the PS performance at the tumor site is of great research interest. Herein, we report a metal-organic framework (ZIF-8, ZIF = zeolitic imidazolate framework) assisted in vivo self-assembly nanoplatform, ZIF-8-PMMA-S-S-mPEG, as an effective tool for organic PS payloads to achieve efficient PDT. Using an organic PS with aggregation-induced emission as an example, under intratumoral bioreduction, PS-loaded ZIF-8-PMMA-S-S-mPEG (PS@ZIF-8-PMMA-S-S-mPEG) was self-assembled into large ordered hydrophobic clusters, which greatly enhance tumor retention and accumulation of the PS. Moreover, hydrophobic ZIF-8 assemblies greatly isolate the loaded PSs from water and improve O2 transport for the PSs to effectively produce 1O2 inside tumors under light irradiation. The organic PS is therefore endowed with optimal tumor accumulation and intratumoral 1O2 production, demonstrating the effectiveness of the developed self-assembly strategy in PDT application.

Reactive oxygen species (ROS) are essential for the regulation of antitumor immune responses, where they could induce immunogenic cell death, promote antigen presentation, and activate immune cells. Here, we report the development of near-infrared (NIR)-driven immunostimulants, based on coupling upconversion nanoparticles with aggregation-induced emission luminogens (AIEgens), to integrate the immunological effects of ROS for enhanced adaptive antitumor immune responses. Intratumorally injected AIEgen-upconversion nanoparticles produce high-dose ROS under high-power NIR irradiation, which induces immunogenic cell death and antigen release. These nanoparticles can also capture the released antigens and deliver them to lymph nodes. Upon subsequent low-power NIR treatment of lymph nodes, low-dose ROS are generated to further trigger efficient T cell immune responses through activation of dendritic cells, preventing both local tumor recurrence and distant tumor growth. The utility of dual-mode pumping power on AIEgen-coupled upconversion nanoparticles offers a powerful and controllable platform to activate adaptive immune systems for tumor immunotherapy.

Molecular theranostic platforms with precise molecular structure and multiple functions hold great promise for cancer therapy. Different from the current strategy to incorporate various components into single entities with the risk of compromised efficacy and poor reproducibility, herein, molecular aggregation-induced emission (AIE) photosensitizers with ingenious integration of AIE fluorophore and cisplatin are facilely synthesized for synergetic anticancer therapy. Through adjusting donor structures coordinated with a cisplatin moiety and balancing the hydrophobic–hydrophilic property, donor–acceptor strength, and intramolecular charge transfer effect, the newly designed AIE photosensitizer TNPT exhibits good cellular uptake with predominant mitochondria location of cancerous cells, high chemotherapeutic efficacy similar to that of cisplatin, and strong reactive oxygen species (ROS) generation capability better than that of chlorin e6 (Ce6). Importantly, TNPT demonstrates synergetic photodynamic and chemotherapy on C6 glioma cells, showing 2.4-fold more potency than cisplatin upon white light irradiation (15 J/cm2). Further cell cycle analysis and apoptosis assay indicate that the photodynamic and chemo-therapeutic functions of TNPT synergistically inhibit DNA replication and cause cell apoptosis. In addition, TNPT exhibits selective uptake on cancerous cells rather than normal cells, contributing to significantly lower cytotoxicity to normal cells as compared to free cisplatin. This study provides a facile strategy to design molecular theranostic agents.

Molecular theranostic platforms with precise molecular structure and multiple functions hold great promise for cancer therapy. Different from current strategy to incorporate various components into single entities with the risk of compromised efficacy and poor reproducibility, herein, molecular aggregation-induced-emission (AIE) photosensitizers with ingenious integration of AIE fluorophore and cisplatin are facilely synthesized for synergetic anticancer therapy. Through adjusting donor structures coordinated with cisplatin moiety and balancing the hydrophobic-hydrophilic prop-erty, donor-acceptor strength, and intramolecular charge transfer effect, the newly designed AIE photosensitizer TNPT exhibits good cellular uptake with predominant mitochondria location of cancerous cells, high chemotherapeutic efficacy similar to cisplatin, and strong reactive oxygen species (ROS) generation capability better than chlorin e6 (Ce6). Im-portantly, TNPT demonstrates synergetic photodynamic and chemo-therapy on C6 glioma cells, showing 2.4-fold more potent than cisplatin upon white light irradiation (15 J/cm2). Further cell cycle analysis and apoptosis assay indicate that the photodynamic and chemo-therapeutic functions of TNPT synergistically inhibit DNA replication and cause cell apop-tosis. In addition, TNPT exhibits selective uptake on cancerous cells rather than normal cells, contributing to significantly lower cytotoxicity to normal cells as compared to free cisplatin. This study provides a facile strategy to design molecular theranostic agents.

In order to promote the development of photodynamic therapy (PDT), undesired side effects like low tumor specificity and the “always-on” phenomenon should be avoided. An effective solution is to construct an adaptive photosensitizer that can be activated to generate reactive oxygen species (ROS) in the tumor microenvironment. Herein, we design and synthesize a supramolecular switch based on a host-guest complex containing a water-soluble pillar[5]arene (WP5) and an AIEgen photosensitizer (G). The formation of the host-guest complex WP5?G quenches the fluorescence and inhibits ROS generation of G. Benefitting from the pH-responsiveness of WP5, the binding site between G and WP5 changes in an acidic environment through a shuttle movement. Consequently, fluorescence and ROS generation of the host-guest complex can be switched on at pH 5.0. This work offers a new paradigm for the construction of adaptive photosensitizers by using a supramolecular method.

The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near-infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF-cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF-cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.

Organic photothermal nanoagents are promising candidates for treating primary tumors and inhibiting metastasis. However, they often exhibit poor photostability, low absorptivity, or limited photothermal conversion efficiency (PCE). Herein, a facile molecular engineering approach to produce efficient organic photothermal molecules is demonstrated. By integrating donor–acceptor structure and molecular motors, a small molecule (TA1) is synthesized with large absorptivity (22.4 L g−1 cm−1), negligible reactive oxygen species generation, high PCE (84.8%), excellent photothermal stability, and good biocompatibility. Furthermore, microfluidics is used to thoroughly study the relationship between the size and process conditions, yielding small uniform nanoparticles (NPs) with a diameter of 44 nm. Importantly, TA1 NPs under near-infrared laser irradiation significantly suppressed primary breast tumor growth and metastasis, both in vitro and in vivo. This study shows that small organic molecule nanoparticles are promising candidates for future cancer nanomedicine.

Precise design of fluorescent molecules with desired properties has enabled the rapid development of many research fields. Among the different types of optically active materials, luminogens with aggregation-induced emission (AIEgens) have attracted significant interest over the past two decades. The negligible luminescence of AIEgens as a molecular species and high brightness in aggregate states distinguish them from conventional fluorescent dyes, which has galvanized efforts to bring AIEgens to a wide array of multidisciplinary applications. Herein, the useful principles and emerging structure–property relationships for precise molecular design toward AIEgens with desirable properties using concrete examples are revealed. The cutting-edge applications of AIEgens and their excellent performance in enabling new research directions in biomedical theranostics, optoelectronic devices, stimuli-responsive smart materials, and visualization of physical processes are also highlighted.