Delivery of functional biomacromolecules into cells is greatly beneficial for therapy, however, this remains to be challenging. Our group has recognized that biomacromolecules (e.g. proteins and nucleic acids) are physically large and thus require large portals of entry. Clathrin or caveolin-mediated endocytosis could provide these cargoes access but are limited by the sizes of resulting endosomes (around 100 nm and 50 nm, respectively), necessitating uptake through a more robust pathway.

We addressed this by opting to exploit macropinocytosis. Usually regarded as a transient, growth factor receptor-mediated, actin-dependent uptake, macropinocytosis is performed by cells to internalize bulk extracellular fluid and materials into large vesicles (≥ 1.0 µm in diameter) called macropinosomes¹. These macropinosomes are commonly believed to be “leaky”, which makes it possible for enclosed materials to escape into the cytosol. We considered these characteristics to be potentially advantageous for intracellular delivery of large biomacromolecules (ex. Nanoparticles, IgG, etc.).

Macropinocytosis has also been suggested to be an entry mechanism for other successful delivery strategies; but by coincidence, instead of by design. We, therefore, aimed to develop a peptide-based strategy that largely induces macropinocytosis to deliver extracellular cargoes into cells. In this presentation, we will present the conceptualization of a macropinocytosis-inducing peptide, based on a previously studied inducer², its applications, and its proposed mechanism.