LAUSR

The combination of hypoxia-promoted photodynamic therapy (PDT) and autophagy modulation has shown strong potential in the treatment of hypoxic tumors. However, there are very few reports on hypoxia-enhanced photosensitizers with multi-band emitted upconversion nanoparticles (UCNPs) to achieve O2 -independent PDT. Here, a novel design was put forward for synergistic PDT and autophagy inhibition to amplify the effect of cancer therapy by a "chase and block" strategy. Specifically, a nanocomposite (UCNPs@FL-MEL) was presented based on co-doped UCNPs. And a hypoxia-sensitive organic photosensitive molecule (denoted as FL) with strong absorption in the UV-vis region was encapsulated in a hydrophobic layer between UCNPs and the amphiphilic polymer DSPE-PEG-COOH. On the one hand, FL can fully utilize the multi-band luminescence spectra of UCNPs under near-infrared (NIR) light irradiation. On the other hand, it can be specifically activated by nitroreductase in the hypoxic tumor microenvironment (TME), which enhances the intersystem crossing process of FL and then increases the production of reactive oxygen species (ROS) at the site of hypoxia, thus realizing hypoxia-promoted PDT and executing the "chase" strategy for cancer therapy. At the same time, the nanosystem was combined with an autophagy-inhibiting melittin pro-peptide (denoted as MEL), which could be triggered by the highly expressed legumain in tumor cells to inhibit the autophagy procedure by disrupting the lysosomal membrane, thus "blocking" the cancer cells from rescuing themselves and amplifying the killing effect of PDT. Both FL and MEL could be specifically activated by TME, which avoids damage to normal tissues. Moreover, the upconversion luminescence imaging of UCNPs offers a tracer function for the treatment, making the system more accurate and effective. Therefore, UCNPs@FL-MEL might be an important reference for the design and development of future nanotherapeutic agents. This article is protected by copyright. All rights reserved.