The unique behaviors of engineered nanomaterials (eNMs) bring many exciting applications, and also raise safety concerns. Zebrafish have been widely used as a model organism for toxicity tests of eNMs. Commonly, the equivalent toxic dose of the drug is estimated by the level of malformation in zebrafish at 5 or 6 days post-fertilization (dpf). However, this method is only suitable for the evaluation of general toxicity. To distinguish the specific aspects of the drug, a much more sensitive approach is needed. Here, we first evaluated the toxicity of NPs that are largely composed of poly(ethylene glycol dimethacrylate-co-methacrylic acid) (P(EGDMA-co-MAA)). Surprisingly, statistical analysis of the data did not show eNMs toxicity in zebrafish embryos with chorions compared with the control. To further determine the effects of P(EGDMA-co-MAA) on the embryonic development of zebrafish, we stripped the chorions of 1-dpf embryos and exposed them to P(EGDMA-co-MAA). As early as 2 dpf, the embryonic mortality and teratogenicity were significantly elevated, suggesting that the chorion acts as a protective barrier against P(EGDMA-co-MAA). In addition, the data imply that P(EGDMA-co-MAA) shows low toxicity in zebrafish larvae (3–5 dpf) because the fish are mature enough to resist damage from eNM exposure. These data suggest that evaluation of eNMs toxicity at different developmental stages of dechorionated in zebrafish is a more sensitive method than more traditional analyses. Furthermore, the mechanism of interactions between eNMs and dechorionated zebrafish 2 dpf should be clarified in future studies to create less toxic eNMs for use as drug-delivery vectors.