Dual‐Functional Nanodroplet for Tumor Vasculature Ultrasound Imaging and Tumor Immunosuppressive Microenvironment Remodeling

Abstract Accurately evaluating tumor neoangiogenesis and conducting precise interventions toward an immune‐favorable microenvironment are of significant clinical importance. In this study, a novel nanodroplet termed as the nanodroplet‐based ultrasound contrast agent and therapeutic (NDs UCA/Tx ) is designed for ultrasound imaging and precise interventions of tumor neoangiogenesis. Briefly, the NDs UCA/Tx shell is constructed from an engineered CMs containing the tumor antigen, vascular endothelial growth factor receptor 1 (VEGFR1) extracellular domain 2–3, and CD93 ligand multimerin 2. The core is composed of perfluorohexane and the immune adjuvant R848. After injection, NDs UCA/Tx is found to be enriched in the tumor vasculature with high expression of CD93. When triggered by ultrasound, the perfluorohexane in NDs UCA/Tx underwent acoustic droplet vaporization and generated an enhanced ultrasound signal. Some microbubbles exploded and the resultant debris (with tumor antigen and R848) together with the adsorbed VEGF are taken up by nearby cells. This cleared the local VEGF for vascular normalization, and also served as a vaccine to activate the immune response. Using a syngeneic mouse model, the satisfactory performance of NDs UCA/Tx in tumor vasculature imaging and immune activation is confirmed. Thus, a multifunctional NDs UCA/Tx is successfully developed for molecular imaging of tumor neoangiogenesis and precise remodeling of the tumor microenvironment.