The molecular weight of a polymer always influences the outcome of any drug delivery system. In this milieu, understanding the effect of molecular weight of polymer in designing an effective drug delivery system has caught a significant attention. Here, in this study, we have systematically examined the effects of molecular weights of metal-free fully alternating semi-aromatic polyester made up of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) monomers (poly(tBGE-alt-PA) copolymer) to design an efficient drug delivery system for cancer therapy. The molecular weights of such polyester greatly influenced the encapsulation efficiency, drug loading capacity, in vitro drug release profile and intracellular drug uptake of different nano-drug carriers, which finally determined its drug delivery efficiency. The anti-tumor therapeutic efficacy of all nano-drug carriers was tested on MIA PaCa-2 cells and maximum cytotoxicity was exhibited in case of poly(tBGE-alt-PA)-DOX nanoparticles of Mn = 9.2 kDa with low IC 50 value. These results were further corroborated with colony forming unit data, where maximum inhibition in MIA PaCa-2 cell proliferation was also found in case of low molecular weight DOX nanoparticles. Hence, we proved that poly(tBGE-alt-PA) copolymer of Mn = 9.2 kDa can be used further in the broader applications of drug delivery. © 2019 Elsevier B.V.