A Genetically Engineered Macrophage-Derived Vesicular Nanodecoy Targeting the CD47/SIRPα Axis for Reinforced Tumor Radioimmunotherapy.

Abstract

Radiotherapy, while effective in tumor treatment, often induces upregulation of CD47 checkpoint expression on malignant cells, activating the CD47-SIRPα "don't eat me" signaling axis to inhibit macrophage-mediated phagocytosis, thereby promoting immune evasion and ultimately compromising therapeutic efficacy. Herein, a radiosensitizer-loaded biomimetic nanodecoy (p@MVs-Sirpα) is constructed by harnessing genetically engineered macrophage-derived vesicles to enhance tumor radioimmunotherapy. p@MVs-Sirpα displays the high surface expression of signal regulatory protein α (SIRPα), enabling it to selectively bind to CD47, a "don't eat me" signal overexpressed on tumor cells post radiotherapy, thereby competitively blocking the CD47/SIRPα immune checkpoint and promoting macrophage-mediated phagocytosis. Additionally, the nanodecoy is loaded with the radiosensitizing agent polyoxometalates (POMs), which further enhance the efficacy of radiotherapy by modulating the tumor immune microenvironment. This dual-function strategy not only facilitates the immune clearance of tumor cells but also potentiates radiotherapy-induced antitumor responses. p@MVs-Sirpα effectively inhibits the progression of established tumors in multiple murine models. Moreover, in tumor rechallenge experiments, robust and durable immune memory was observed, indicating long-term protection against tumor relapse. Collectively, this study provides a promising proof-of-concept for employing genetically engineered vesicle-based nanodecoy to disrupt radiation-induced immune escape and augment the therapeutic outcomes of radioimmunotherapy.