Nanoparticles for Manipulation of the Developmental Wnt, Hedgehog, and Notch Signaling Pathways in Cancer

The Wnt, Hedgehog, and Notch signaling pathways play a crucial role in early development and the maintenance of adult tissues. When dysregulated, these developmental signaling pathways can drive the formation and progression of cancer by facilitating cell survival, proliferation, and stem-like behavior. While this makes these pathways promising targets for therapeutic intervention, their pharmacological inhibition has been challenging due to the substantial complexity that exists within each pathway and the complicated crosstalk that occurs between the pathways. Recently, several small molecule inhibitors, ribonucleic acid (RNA) molecules, and antagonistic antibodies have been developed that can suppress these signaling pathways in vitro, but many of them face systemic delivery challenges. Nanoparticle-based delivery vehicles can overcome these challenges to enhance the performance and anti-cancer effects of these therapeutic molecules. This review summarizes the mechanisms by which the Wnt, Hedgehog, and Notch signaling pathways contribute to cancer growth, and discusses various nanoparticle formulations that have been developed to deliver small molecules, RNAs, and antibodies to cancer cells to inhibit these signaling pathways and halt tumor progression. This review also outlines some of the challenges that these nanocarriers must overcome to achieve therapeutic efficacy and clinical translation.