A promising paradigm for drug administration that has garnered increasing attention in recent years is the direct transfer (DT) of nanoparticles for transcellular drug delivery. DT requires direct cell-cell contact and facilitates unidirectional and bidirectional matter exchange between neighboring cells. Consequently, DT enables fast and deep penetration of drugs into the targeted tissues. This comprehensive review discusses the direct transfer concept, which can be delineated into the following three distinct modalities: membrane contact-direct transfer, gap junction-mediated direct transfer (GJ-DT), and tunneling nanotubes-mediated direct transfer (TNTs-DT). Further, the intercellular structures for each modality of direct transfer and their respective merits and demerits are summarized. The review also discusses the recent progress on the drugs or drug delivery systems that could activate DT.
Keywords: Direct transfer; cell membrane; gap junctions; nanoparticle; tunneling nanotubes.