An Organo–Inorganic Hybrid Nanomaterial to Disrupt Multicellular Communication within Tumor Microenvironment

Abstract The lack of clear identification or understanding of the key perpetrators activating the tumor microenvironment (TME) impedes development of TME-modulating therapeutic strategies that could overcome the challenges associated with tumor growth, metastasis, and therapy resistance. Here, we report the development of a hybrid nanomaterial designed to genetically silence one key regulator, IGFBP2 (insulin-like growth factor binding protein 2), responsible for multicellular crosstalk within the TME. We demonstrated that silencing of IGFBP2 by this hybrid nanomaterial suppressed angiogenesis, stromal activation, and tumor cell phenotypes both in vitro and in vivo in preclinical models of ovarian cancer. Mechanistically, the hybrid nanomaterial utilizes the caveolae-mediated intracellular uptake pathway rather than a mixture of clathrin and caveolin as seen with a nonhybrid counterpart. Given the role of IGFBP2 as a prognostic factor for several cancers, and the absence of any small molecule inhibitor of IGFBP2, the current strategy may be exploited as a promising and generalized approach to target the TME and improve therapeutic outcomes in numerous cancers, including ovarian cancer