Engineering photosensitizers into stimuli-responsive supramolecular nanodrugs allows enhanced spatiotemporal delivery and controllable release of photosensitizers, which is promising for dedicated and precise tumor photodynamic therapy. Complicated fabrication for nanodrugs with good tumor accumulation capability and the undesirable side-effects caused by the drug components retards the application of PDT in vivo. The fact that extracellular adenosine triphosphate (ATP) is overexpressed in tumor tissue has been overlooked in fabricating nanomedicines for tumor-targeting delivery. Hence, herein we present metal-free helical nanofibers formed in aqueous solution from the coassembly of a cationic porphyrin and ATP as a nanodrug for PDT. The easily accessible and compatible materials and simple preparation enable the nanodrugs with potential in PDT for cancer. Compared to the cationic porphyrin alone, the porphyrin–ATP nanofibers exhibited enhanced tumor-site photosensitizer delivery through whole-body blood circulation. Overexpressed extracellular ATP stabilizes the porphyrin–ATP nanodrug within tumor tissue, giving rise to enhanced uptake of the nanodrug by cancer cells. The enzyme-triggered release of photosensitizers from the nanodrugs upon biodegradation of ATP by intracellular phosphatases results in good tumor therapeutic efficacy. This study demonstrates the potential for employing the tumor microenvironment to aid the accumulation of nanodrugs in tumors, inspiring the fabrication of smart nanomedicines.

As the most successful clinically approved photosensitizers, porphyrins have been extensively employed in the photodynamic therapy (PDT) of cancers. However, their poor water solubility, aggregation-induced self-quenching on ROS generation, and a low tolerance for a hypoxic condition usually result in unsatisfied therapeutic outcomes. Therefore, great efforts have been dedicated to improving the PDT efficacy of porphyrin-type photosensitizers in treating hypoxic tumors, including combination with additional active components or therapies, which can significantly complicate the therapeutic process. Herein, we report a novel water-soluble porphyrin with O-linked cationic side chains, which exhibits good water solubility, high photostability, and significantly enhanced ROS generation efficacy in both type-I and type-II photodynamic pathways. We have also found that the end charges of side chains can dramatically affect the ROS generation of the porphyrin. The cationic porphyrin exhibited high in vitro PDT efficacy with low IC50 values both in normoxia and hypoxia. Hence, during in vivo PDT study, the cationic porphyrin displayed highly effective tumor ablation capability. This study demonstrates the power of side-chain chemistry in tuning the photodynamic property of porphyrin, which offers a new effective strategy to enhance the anticancer performance of photosensitizers for fulfilling the increasing demands for cancer therapy in clinics.

Due to their excellent electronic and optical properties, porphyrins are extensively studied conjugated macrocycles in supramolecular chemistry for assembling functional nanomaterials. The aggregation of monomers plays a significant role in...

Programmed death ligand 1 (PDL1) is a specific molecular target for the diagnosis and immunotherapy of solid tumors. PET imaging can be used for noninvasive assessments of PDL1 expression in tumors to aid in therapy selection. The most frequently reported small-molecule radiotracer of PDL1 is limited by low imaging specificity, short residence time, and singular functionality. Here, we combined a biocompatible melanin nanoprobe with the PDL1-binding peptide WL12 to construct a novel radiotracer, 124I-WPMN, to enhance PDL1 targeting. The radiochemical purity of 124I-WPMN was >95%, and uptake in A549PDL1 cells was 1.49 ± 0.08% at 2 h. The uptake was blocked by WL12 (0.39 ± 0.03%, P < 0.0001). This novel radiotracer showed a higher affinity for PDL1 (K d = 18.5 nM) than 68Ga-NOTA-WL12 (K d = 24.0 nM). Micro-PET/CT imaging demonstrated specific uptake and a high signal-to-noise ratio in an A549PDL1 xenograft mouse model with a tumor-to-muscle ratio of 27.31 ± 7.03 at 2 h. The levels increased or remained steady for more than 72 h, and tumor uptake was significantly higher than 68Ga-NOTA-WL12, at 6.08 ± 0.62 at 2 h. Prolonged retention of 124I-WPMN makes it possible to conduct PET/MRI imaging over long periods and to perform various imaging techniques. A clear advantage of 124I-WPMN over 68Ga-NOTA-WL12 was observed for PDL1-targeted PET imaging after nanoparticle modification, supporting the utility of 124I-WPMN PET imaging as an effective diagnostic tool for optimizing PDL1-targeted therapies.

Delayed fluorescence molecules have important applications in time‐resolved luminescence imaging (including lifetime imaging) systems. However, existing approaches of generating delayed fluorescence in organic molecules rely on triplets as long‐lived intermediate states. As such, this triplet‐based delayed fluorescence can be severely plagued by its oxygen sensitivity. As the presence of oxygen or ambient air can hardly be avoided in living biosystems, oxygen‐insensitive delayed fluorescence is highly desirable. Herein, a new pathway is reported for oxygen‐insensitive delayed fluorescence which is produced only within the singlet manifold. Such an example is found in a cyto‐compatible and water‐soluble trimethine cyanine dye C3T‐H, which bears a very high molar extinction coefficient and a narrow‐band red emission. It is demonstrated that this dye exhibits notable delayed fluorescence which cannot be diminished by the presence of oxygen or ambient air. Time‐resolved imaging of living cells in the presence of oxygen is successfully achieved. Through quantum chemical calculations, a nonemissive dark‐state structure in the S1 state is found to be thermodynamically viable (energy barrier ≈8 kcal mol−1) through the molecular twisting around the trimethine bridge of C3T‐H, which serves as a “reservoir” of the excitation energy to enable the oxygen‐insensitive delayed fluorescence.