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In our previous study, target drug delivery and treatment of malignant tumors have been achieved by using platelets as carriers loading nano-chemotherapeutic agents (ND-DOX). However, drug release from ND-DOX-loaded platelets is dependent on negative platelet activation by tumor cells, whose activation is not significant enough for the resulting drug release to take an effective anti-tumor effect. Exploring strategies to proactively manipulate the controlled release of drug-laden platelets is imperative. The present study innovatively revealed that photodynamic action can activate platelets in a spatiotemporally controlled manner. Consequently, based on the previous study, platelets were used to load iron oxide-polyglycerol-doxorubicin-chlorin e6 composites (IO-PG-DOX-Ce6), wherein the laser-triggered drug release ability and anti-tumor capability were demonstrated. The findings suggested that IO-PG-DOX-Ce6 could be stably loaded by platelets in high volume without any decrease in viability. Importantly and interestingly, drug-loaded platelets were significantly activated by laser irradiation, characterized by intracellular ROS accumulation and up-regulation of CD62p. Additionally, scanning electron microscopy (SEM) and hydrated particle size results also showed a significant aggregation response of laser irradiated-drug-loaded platelets. Further transmission electron microscopy (TEM) measurements indicated that the activated platelets released extracellularly their cargo drug after laser exposure, which could be taken up by co-cultured tumor cells. Finally, the co-culture model of drug-loaded platelets and tumor cells proved that laser-triggered delivery system of platelets could effectively damage the DNA and promote apoptosis of tumor cells. Overall, the present study discovers a drug-loaded platelets delivery using photodynamic effect, enabling laser-controlled intelligent drug delivery and anti-tumor therapy, which provides a novel and feasible approach for clinical application of cytopharmaceuticals. What is the context? 1. Platelets were applied to load IO-PG-DOX-Ce6, wherein the laser-triggered drug release and anti-tumor effect were investigated in vitro. 2. The findings indicated that IO-PG-DOX-Ce6 could be stably loaded by platelets in high volume without any decrease in viability, which may attribute to the activation of autophagy in platelets. 3. IO-PG-DOX-Ce6-loaded platelets could be significantly activated by laser irradiation (690 nm). 4. Activated platelets released extracellularly their cargo drug after laser exposure, which could be taken up by co-cultured tumor cells 5. The co-culture model of drug-loaded platelets and tumor cells proved that the laser-triggered delivery system of platelets could effectively damage the DNA and promote apoptosis of tumor cells. What is new? 1. Platelets could be utilized as the vehicle to load photosensitizer-loaded-nano-drug. 2. Photodynamic action can activate platelets in a spatiotemporally controlled manner, which could be a tool to regulate the activation of platelets. 3. The laser-triggered activation of drug-loaded platelets allows for target release of cargo. 4. The limitation of the current research is that only in vitro experiments were carried out to demonstrate our conclusions. What is impact? The present work provides a novel and feasible approach for the clinical application of cytopharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Non-small-cell lung cancer (NSCLC) is the most common malignant lung tumor and is difficult to be eradicated due to its immunosuppressive microenvironment. Chlorin e6 (Ce6)-mediated photodynamic therapy (PDT) could improve immunogenicity while destroying malignant tumor cells. However, the clinic application of Ce6-mediated PDT is limited by Ce6's poor water solubility and insufficient accumulation in lung cancer. To address this issue, Ce6 was loaded onto functionalized iron oxide nanoparticles linked with glucose to improve the distribution of Ce6 in lung cancer. Materials and results: The results of transmission electron microscopy (TEM), UV–Vis spectrophotometry, dynamic light scattering and near-infrared (NIR) spectroscopy confirmed the successful preparation of the composites. Confocal and flow cytometry showed IO–PG–GLU–Ce6 significantly enhanced the uptake of Ce6 by lung cancer cells and produced more reactive oxygen species (ROS) under NIR light irradiation. In addition, the detection of cell viability, proliferation and apoptosis indicated IO–PG–GLU–Ce6 achieved stronger photo-toxicity to lung cancer cells. Moreover, IO–PG–GLU–Ce6 treatment effectively damaged the DNA of lung cancer cells and thereby activated STING, up-regulated the expression of IFN-β, HMGB1 and HSP90, indicating augmented immunogenicity of lung cancer cells. Further results of in vivo, organ imaging and tissue fluorescence sections demonstrated IO–PG–GLU–Ce6 significantly improved the distribution of Ce6 in tumor tissues of lung cancer-bearing mice as well. Finally, the findings of in vivo study and immunohistochemistry confirmed the better efficacy of IO–PG–GLU–Ce6. HE staining results of vital organs suggested that the composites were less toxic. Conclusion: In conclusion, Ce6 loaded by functionalized iron oxide nanoparticles linked with glucose exhibited both target photodynamic efficacy and the ability to enhance its immunogenicity in lung cancer. This study provides a promising strategy for augment of the targeting delivery of Ce6 and its mediated photodynamic and immunotherapy. [ABSTRACT FROM AUTHOR]

The tumor-associated macrophage (TAM) serves as an immunosuppressive agent in the malignant tumor microenvironment, facilitating the development and metastasis of lung cancer. The photodynamic effect destabilizes cellular homeostasis owing to the generation of reactive oxygen species (ROS), resulting in the enhanced pro-inflammatory function of immunocytes. In our previous study, the Ce6-mediated photodynamic effect was found to have kept the viability of macrophages and to remodel them into the M1 phenotype. However, the mechanism remains unrevealed. The present study now explores the mechanism of photodynamic therapy (PDT)-mediated reprogramming of macrophages. As expected, Ce6-mediated PDT was capable of generating reactive oxygen species, which was continuously degraded, causing "low intensity" damage to DNA and thereby triggering subsequent DNA damage response in macrophages. The autophagy was thus observed in Ce6-treated macrophages and was shown to protect cells from being photodynamically apoptotic. More importantly, Ce6 PDT could activate the stimulator of interferon genes (STING) molecule, a sensor of DNA damage, which could activate the downstream nuclear factor kappa-B (NF-κB) upon activation, mediating the polarization of macrophages towards the M1 phenotype thereupon. In addition, inhibition of ROS induced by PDT attenuated the DNA damage, STING activation, and M1-phenotype reprogramming. Furthermore, the silence of the STING weakened Ce6 treatment-mediated M1 remodeling of macrophages as well. Altogether, these findings indicate the Ce6-induced photodynamic effect polarizes macrophages into an M1 phenotype through oxidative DNA damage and subsequent activation of the STING. This work reveals the crucial mechanism by which photodynamic therapy regulates the macrophage phenotype and also provides a novel intervenable signaling target for remodeling macrophages into the M1 phenotype. [ABSTRACT FROM AUTHOR]