A photo-activable nano-agonist for the two-signal model of T cell in vivo activation.

The two-signal model of T cell activation has helped shape our understanding of the adaptive immune response for over four decades. According to the model, activation of T cells requires a stimulus through the T cell receptor/CD3 complex (signal 1) and a costimulatory signal 2. Stimulation of activatory signals via T cell agonists has thus emerged. However, for a robust T cell activation, it necessitates not only the presence of both signal 1 and signal 2, but also a high signaling strength. Herein, we report a photo-activable nano-agonist for the two-signal model of T cell in vivo activation. A UV-crosslinkable polymer is coated onto upconversion nanoparticles with satisfactory NIR-to-UV light conversion efficiency. Then dual signal molecules, i.e., signal 1 and signal 2, are conjugated to the polymer end to yield the photo-activable T cell nano-agonist. In melanoma and breast cancer models, photo-activable nano-agonist could bind onto corresponding activatory receptors on the surface of T cells, but has limited activity without the application of NIR light (absence of photo-crosslinking of receptors and consequently a poor signaling strength). While when the NIR light is switched on locally, T cells in tumor are remarkably activated and kill tumor cells effectively. Moreover, we do not observe any detectable toxicities related to the photo-activable nano-agonist. We believe with two activatory signals being simultaneously strengthened by local photo-switched crosslinking, T cells realize a robust and selective activation in tumor and, consequently contribute to an enhanced and safe tumor immunotherapy.

Multifunctional Microspheres Dual-Loaded with Doxorubicin and Sodium Bicarbonate Nanoparticles to Introduce Synergistic Trimodal Interventional Therapy.

Lactic acid in the tumor microenvironment is highly correlated with the prognosis of tumor chemoembolization, but there are limited clinical strategies to deal with it. To improve the efficacy, NaHCO3 nanoparticles are innovatively introduced into drug-loaded microspheres to neutralize lactic acid in the tumor microenvironment. Here we showed that multifunctional ethyl cellulose microspheres dual-loaded with doxorubicin (DOX) and NaHCO3 nanoparticles (DOX/NaHCO3-MS) presented excellent antitumor effects by improving the pH of the tumor microenvironment. The homeostasis of the tumor microenvironment was continuously disturbed due to the sustained release of NaHCO3 nanoparticles, which also led to a significant increase in tumor cell apoptosis (compared with the control and DOX-MS groups). We also showed that the administration of DOX/NaHCO3-MS via the hepatic artery in a rabbit model of VX2 orthotopic liver cancer resulted in optimal antitumor efficacy, and the area of tumor necrosis at the embolization site was significantly increased and the proliferation of tumor cells was significantly weakened. The designed DOX/NaHCO3-MS exhibited strong synergistic antitumor effects of embolization, chemotherapy, and tumor microenvironment improvement. The present microspheres provided a strategy for the enhancement of the chemoembolization of hepatocellular carcinoma, which could also be extended to other clinical embolization treatments for blood-rich solid tumors.