This study focuses on the preparation and characterization of platelet membrane biomimetic nanocarriers (P-PLGA NPs) and investigates their interactions with the transplacental barrier. Poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) were coated with platelet membrane (PLTM) to construct P-PLGA NPs. Additionally, fluorinated polyethylenimine (F-PEI) was grafted onto PLGA NPs to prepare F-PEI-PLGA NPs, which were compared with PLGA NPs. In vitro placental barrier cell models using human choriocarcinoma cells (BeWo b30) and in vivo pregnancy animal models using ICR mice were utilized to evaluate the transplacental barrier efficiency of the PLGA NPs with different surface modifications. The results demonstrated that all three types of nanoparticles could accumulate in the uterus and placenta. The transplacental barrier efficiency of F-PEI-PLGA NPs was found to be the highest at 4 h, while P-PLGA NPs exhibited the highest transplacental barrier efficiency at 12 and 24 h. Furthermore, there were no significant effects on the main organs, structure, and quantity of uterine spiral arteries, indicating the safety of the nanoparticles (NPs). P-PLGA NPs are expected to be a safe and effective nano-delivery system for perinatal drug delivery. This study provides insights into the transplacental barrier mechanism of NPs with different surface characteristics.