Biodegradable nanoplastics potentiate cadmium quantum dot developmental neurotoxicity in embryonic stem cells via synergistic interactions.

Biodegradable nanoplastics like poly(ε-caprolactone) (PCL) are increasingly used as green alternatives, yet their interactions with environmental co-occurrence engineered nanomaterials like cadmium-containing quantum dots (Cd-QDs) remain poorly understood. Here, using a mouse embryonic stem cell differentiation model, we showed that Cd-QDs and poly(ε-caprolactone) nanoparticles (PCL-NPs) at individually subcytotoxic concentrations (0.076 and 1.52 mg/L, respectively) synergistically impaired neural differentiation. The observed mixture toxicity exceeded concentration-addition model predictions. Fluorescence spectroscopy, together with particle characterization in differentiation medium, supported physicochemical association and heteroaggregation between PCL-NPs and Cd-QDs, accompanied by a 2.3-fold increase in intracellular Cd-QD accumulation. Mechanistically, co-exposure triggered sequential membrane damage, including ROS-induced lipid peroxidation disrupted membrane integrity, increased fluidity/permeability, inhibited Ca²⁺-ATPase and Na⁺-K⁺-ATPase, and impaired ABC efflux pumps (P-gp/MRP2). These changes were associated with reduced Neurod1 and Map2 expression and impaired neural differentiation. Rifampicin intervention alleviated membrane dysfunction and restored neural differentiation, supporting the functional involvement of transporter-associated cellular defense while not excluding other protective pathways. Collectively, these findings demonstrate that PCL-NPs can potentiate Cd-QD toxicity by enhancing intracellular accumulation and disrupting interconnected membrane and efflux-defense processes, revealing mixture effects that may be overlooked by conventional single-material toxicity assessments.