Cell-Derived Nanocarriers for Monocyte-Mediated Therapeutic Delivery: Concept and Challenges

Nano-delivery has been largely focused on ligand-based navigational targeting, but several common limitations have been recognized. First, the same targeting ligand can be sporadically expressed by unintended cells and tissues across different temporal and spatial contexts. Second, clearance from blood circulation via the liver, kidney, lung, and spleen is largely uncontrollable, in addition to nonspecific uptake by immune cells during circulation or tissue accumulation. Accordingly, inherent characteristics of cells have recently been utilized as alternative strategic points for delivery. Cell-derived nanocarriers utilize plasma membranes as modulators of targeting and delivery mechanisms, including cell hitchhiking to alter carrier behavior, reprogram phenotypes, and enable drug hand-over. The membrane mediates contact with target cells in a manner analogous to cell-cell interactions, thereby enabling physical bridging between cells and natural homing to peer cells, in addition to user-specified molecular display through mother cell expression or chemical conjugation. Here, cell-derived nanocarriers for therapeutic delivery (CDNTD) are reviewed with emphasis on their mechanistic basis, distinctions from synthetic nanoparticles, and therapeutic potential. We recently introduced spleen-mediated delivery strategies that employ resident monocytes as second therapeutic carriers following uptake of primary nanocarriers. In this way, the natural targeting behavior of monocytes in response to inflammatory cues enhances payload delivery efficiency to ischemic sites. Future directions of CDNTD research are also discussed with respect to clinical translation.