To exert their therapeutic effects, nanoparticles (NPs) often need to travel into the tissues composed of multilayered cells. Accumulative evidence has revealed the crucial role of transcellular transport route (entry into one cell, exocytosis, and re‐entry into another) in this process. While NP endocytosis and subcellular transport are intensively characterized, the exocytosis and re‐entry steps are poorly understood, which becomes a barrier for NP delivery into complex tissues. Here, the authors term the exocytosis and re‐entry steps together as intercellular exchange. A collagen‐based three‐dimension assay is developed to specifically quantify the intercellular exchange of NPs, and distinguish the contributions of several potential mechanisms. The authors show that NPs can be exocytosed freely or enclosed inside extracellular vesicles (EVs) for re‐entry, while direct cell–cell contact is hardly involved. EVs account for a significant fraction of NP intercellular exchange, and its importance in NP transport is demonstrated in vitro and in vivo. While freely released NPs engage with the same receptors for re‐entry, EV‐enclosed ones bypass this dependence. These studies provide an easy and precise system to investigate the intercellular exchange stage of NP delivery, and shed the first light in the importance of EVs in NP transport between cells and into complex tissues.
Inefficient extravasation and penetration in solid tissues hinder the clinical outcome of nanoparticles (NPs). Recent studies have shown the extravasation and penetration of NPs in solid tumor are mostly achieved via an active transcellular route. Numerous efforts are devoted to elucidate the endocytosis and subcellular trafficking of NPs. However, how they exit from one cell and re-enter into neighboring ones (termed intercellular exchange) remains poorly understood. The previous study showed that a significant portion of NPs are transferred inside extracellular vesicles (EVs). Inhibition of EV biogenesis significantly reduces tumor accumulation and vascular penetration of various NPs in vivo. Here, a manual chemical screen is performed with this assay, which identifies that LDN-214117 (an inhibitor for activin receptor-like kinase-2, ALK-2) as an agonist of NP intercellular exchange. LDN-214117 is showed to regulate the intercellular exchange by increasing the EV biogenesis via bone morphogenetic protein-mitogen-activated protein kinase (BMP-MAPK) signaling pathway. LDN-214117 treatment further enhances tumor accumulation and vascular penetration of a variety of NPs in multiple tumor models, which improves their antitumor efficacy. Overall, the identification of a novel chemical compound with intercellular exchange assay is showcase to modulate EV-mediated transport, thus boosting the delivery and therapeutic efficacy of nanomaterials.
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