A tumor microenvironment-responsive Zr-MOF nanosystem for co-delivering siHIF-1α and triptolide enhances photodynamic therapy in esophageal cancer by amplifying ROS generation and reversing hypoxia.

In addition to early diagnosis and on-time treatment, the adoption of new therapeutic strategies is of great significance for improving the clinical outcomes of patients with esophageal cancer. Although emerging therapies such as photothermal and photodynamic therapy (PDT) can precisely eliminate cancer cells and are alternative strategies to conventional treatments, hypoxia status of solid tumors have hindered their application. In recent years, nanoplatforms have been developed to address these limitations and improve the efficacy and safety of treatments. In addition, triptolide (TPL) and HIF-1α silencing may have potential value in cancer treatment by regulating oxidative stress. Inspired by these findings, we designed a cancer cell membrane-camouflaged porphyrin (photosensitizer) metal-organic framework (Zr-MOF@CM) for the co-delivery of TPL and HIF-1α small interfering RNA (siRNA) into tumor cells and tissues. The nanoparticles (TPL/siHIF-1α@Zr-MOF@CM) achieved targeted drug/gene/PDT synergistic therapy for esophageal cancer. This portable "all-in-one" drug delivery system exhibited good biocompatibility, sensitive pH-dependent drug release, and effective phagocytosis by esophageal cancer Kyse-30 cells. In addition, the nanoparticles produced large amounts of ROS and released drugs under near-infrared light (660 nm) irradiation, which significantly increased the apoptosis of esophageal cancer cells. Meanwhile, TPL and siHIF-1α released from the nanoparticles alleviated the hypoxic condition, further improving the PDT effect. In vivo experiments confirmed that TPL/siHIF-1α@Zr-MOF@CM maintained a long circulation time in tumor-bearing mice, specifically targeted the tumor site, and played a synergistic role with PDT to effectively reduce tumor growth. Importantly, TPL/siHIF-1α@Zr-MOF@CM exhibited a favorable biosafety profile in vitro and in vivo. This nanosystem is suitable for enhancing oxidative damage at tumor sites and is instructive for future design of PDT-dependent nanoplatforms.