Polyester nanomaterials have been widely used in drug delivey application from a longer period of time. This study reports the synthesis of metal-free semi-aromatic polyester (SAP) nanomaterial for drug delivery and evaluate its in vivo acute and systemic toxicity for potential clinical application. The ring opening coplymerization of commercially available cyclohexene oxide (CHO) and phthalic anhydride (PA) monomers was carried out to synthesize fully alternating poly(CHO-co-PA) copolymer using metal-free activators. The obtained low Mn SAP was found to be biocompatible, hemocompataible and biodegradable nature. This copolymer was first-time used to fabricate curcumin (CUR) loaded nanoparticles (NPs). These NPs were physicochemically characterized by thermogravimetric analyzer (TGA), X-ray diffraction (XRD), and UV/visible spectrophotometer analysis. Further, these negatively charged core-shell spherical NPs exhibited slow sustained release behavior of CUR with anomalous transport and further displayed its higher intracellular uptake in SiHa cells at different time-periods compared to free CUR. In vitro anti-cancer therapeutic effects of free CUR and poly(CHO-alt-PA)-CUR NPs were evaluated on different cancer cells. We observed the increased cytotoxicity of CUR NPs with low IC50 values compared to free CUR. These results were further substantiated with ex vivo data where, a significant reduction was observed in CUR NPs treated tumor spheroid's size as compared to free CUR. Furthermore, the different doses of metal-free poly(CHO-alt-PA) nanomaterial were tested for its acute and systemic toxicity in BALB/c mice. We did not observe any significant toxicity of tested nanomaterial on vital organs, blood cells and the body weight of mice. Our study suggest that this metal-free SAP nanomaterial can be used for potential clinical application. © 2019 Elsevier B.V.