A Dual Role for the Placenta and Human Amniotic Epithelial Cells in HER3-Targeted Nanotherapy

Background HER3-targeted therapies are developing to clinical trials, while late pregnancy and earlier-onset breast neoplasm have increased the chance of overlap between childbearing age and cancer incidence. While more cancer patients of childbearing age may be exposed to these agents, considering HER3 expression and interactions within placental tissues is crucial for maternal and fetal safety. Methods Human placentas from healthy deliveries were used to isolate human amniotic epithelial cells (hAECs) and prepare amniotic membrane and umbilical cord sections. HER3 expression was analyzed in tissues, cells, and exosomes by multiplex immunofluorescence, flow cytometry, and immunoblot. The HER3-targeted nano-capsomere HPK2.0 and its nucleic acid-complexed form, HerLLAA, were synthesized and assessed by dynamic light scattering, and impact on hAEC viability was evaluated by metabolic assay. HPK uptake, release, and intracellular trafficking were examined using pulse-chase quantification and time-resolved imaging. Results Freshly isolated hAECs exhibited epithelial morphology and heterogeneous stemness and mesenchymal marker expression, with a substantial HER3-positive population. HER3 was strongly localized to the amniotic membrane epithelial layer and was enriched in the umbilical cord endothelium compared to vessel wall and Wharton’s jelly. hAEC-derived extracellular vesicles displayed stable size profiles and contained HER3. HPK2.0 and HerLLAA formed stable nano-structures without inducing cytotoxicity on hAECs. Functionally, hAECs rapidly internalized HPK2.0 and HerLLAA and released it in a dose- and time-dependent manner, consistent with regulated intracellular trafficking rather than long-term retention. Conclusions The amniotic membrane, umbilical cord, hAECs, and their exosomes express HER3 and actively interact with HER3-targeted nanotherapeutics. HPK2.0 and HerLLAA undergoes regulated uptake and release without cytotoxicity, underscoring both safety considerations during pregnancy and the potential for HER3-mediated placental and fetal drug delivery.