Quercetin-ferrum nanoparticles enhance photothermal therapy by modulating the tumor immunosuppressive microenvironment.

Photothermal therapy (PTT) was reported to induce synergistic immunogenic cell death (ICD) which may convert tumor cells into "therapeutic vaccines". However, this is often insufficient to prevent tumor recurrence, in part because of the immunosuppressive microenvironment in tumors. Therefore, remodeling tumor microenvironment is of great importance to enhance the therapeutic efficacy of PTT. We herein fabricated a versatile nano-photosensitizer by assembling quercetin and Ferrum ion (QFN). The released quercetin from QFN could reduce programmed death ligand 1 (PD-L1) in tumor cells by inhibiting the phosphorylation of JAK2 and STAT3, and reshape extracellular matrix (ECM) by down-regulating α-SMA+ fibroblast in tumors. Moreover, QFN could capture tumor antigen and deliver it to the tumor-draining lymph nodes after PTT, which further enhanced the activation of antigen-presenting cells. As a result, QFN-based PTT eliminated melanoma and induced long-term immune memory to prevent tumor metastasis and recurrence. This study provides an effective and translationally feasible photothermic agent for photothermal/immunotherapy. STATEMENT OF SIGNIFICANCE: The efficacy of photothermal therapy (PTT) in cancer treatment is often limited by the immunosuppressive microenvironment in tumors. Herein, we prepared a versatile photosensitizer by assembling quercetin and Ferrum ion (QFN). Upon near-infrared light irradiation, QFN-PTT induced cancer cells destruction and tumor antigen release. QFN then captured antigen and delivered it to the tumor-draining lymph nodes, thus promoting dendritic cell maturation and T cells activation. Quercetin released from QFN in tumors improved T cells infiltration and activation in tumor by regulating immunosuppressive microenvironment. The QFN-PTT-treated mice exhibited significantly elongated survival time, and gained strong anti-tumor immune memory to prevent tumor metastasis and recurrence. Thus, this work provided a simple and versatile photothermic agent, and it has important implications for designing effective and translationally feasible photosensitizers for PTT.

A Two-Pronged Strategy for Enhanced Deep-Tumor Penetration and NIR-II Multimodal Imaging-Monitored Photothermal Therapy.

The second near-infrared (NIR-II)-induced photothermal therapy (PTT) has attracted a great deal of attention in recent years due to its non-invasiveness and because it uses less energy. However, the penetration of photothermal agents into solid tumors is seriously impeded by the dense-tumor extracellular matrix (ECM) containing cross-linked hyaluronic acid (HA), thereby compromising the ultimate therapeutic effects. Herein, acid-labile metal-organic frameworks were employed as nanocarriers to efficiently mineralize hyaluronidase (HAase) and encapsulate Ag2S nanodots by a one-pot approach under mild conditions. The obtained nanocomposites (AHZ NPs) maintained enzyme activity and changed in size to prolong blood circulation and complete delivery of the cargo to the tumor. Moreover, the released HAase could specifically break out the HA to loosen ECM and enable the Ag2S nanodots to breeze through the tumor matrix space and gain access to the deep tumor. Under near-infrared laser irradiation, the AHZ NPs displayed remarkable fluorescence, outstanding photoacoustic signals, and excellent photothermal properties in the whole tumor. This work offers a promising two-pronged strategy via a decrease in nanoparticle size and the degradation of dense ECM for NIR-II multimodal imaging-guided PTT of deep tumors.

Synergizing Upconversion Nanophotosensitizers with Hyperbaric Oxygen to Remodel the Extracellular Matrix for Enhanced Photodynamic Cancer Therapy.

Photodynamic therapy (PDT) holds great promise as a noninvasive and selective cancer therapeutic treatment in preclinical research and clinical practice; however, it has limited efficacy in the ablation of deep-seated tumor because of hypoxia-associated circumstance and poor penetration of photosensitizers to cancer cells away from the blood vessels. To tackle the obstacles, we propose a therapeutic strategy that synergizes upconversion nanophotosensitizers (UNPSs) with hyperbaric oxygen (HBO) to remodel the extracellular matrix for enhanced photodynamic cancer therapy. The UNPSs are designed to have an Nd3+-sensitized sandwiched structure, wherein the upconversion core serves as light transducers to transfer energy to the neighboring photosensitizers to produce reactive oxygen species (ROS). With HBO, photodynamic process can generate abundant ROS in the intrinsically hypoxic tumor. It is revealed for the first time that HBO-assisted PDT decomposes collagen in the extracellular matrix of tumor and thus facilitates the diffusion of oxygen and penetration of UNPSs into the deeper area of tumor. Such a synergic effect eventually results in a significantly enhanced therapeutic efficacy at a low laser power density as compared with that using UNPSs alone. In view of its good biosafety, the HBO-assisted and UNPSs-mediated PDT provides new possibilities for treatment of solid tumors.