P-glycoprotein exofection between fetal and maternal cells as a mechanism of intercellular material transfer at the feto maternal interface

Cells can recover lost protein functions through a process we term exofection, in which extracellular vesicles deliver functional molecular cargo to recipient cells and transiently reprogram their activity. Here we show that exosomes derived from fetal chorion trophoblast cells (CTCs) restore P-glycoprotein (P-gp) efflux transporter function in inflammation-impaired maternal decidual cells (DECs) at the feto-maternal interface. CTCs maintain high P-gp expression under inflammatory stress, whereas DECs exhibit marked downregulation of transporter genes and proteins. Proteomic analysis revealed that CTC-derived exosomes package P-gp as a stable cargo that enters DECs through clathrin- and heparan sulfate–dependent uptake pathways. Delivery of CTC exosomes reinstated P-gp abundance and efflux capacity in LPS-stimulated or P-gp-deficient DECs, as shown by calcein efflux and immunofluorescence assays. In pregnant P-gp knockout mice, exosome treatment restored systemic clearance of the P-gp substrate tacrolimus and improved pharmacokinetic parameters. These findings establish exofection as a naturally occurring mechanism of transporter rescue at the feto-maternal interface, where fetal exosomes compensate for inflammation-induced maternal loss of efflux capacity. By restoring P–gp–mediated barrier function, exofection provides a protective strategy that limits the accumulation of xenobiotics and cytokines in maternal tissues and safeguards the fetus. This work reveals a previously unrecognized form of intercellular communication with broad implications for fetal protection, placental biology, cellular engineering, and the delivery of therapeutic proteins. One Sentence Summary Exofection is identified as a novel mechanism of transient cellular engineering via exosome-mediated functional protein delivery between cells.