​Nanoparticles (NPs) that combine stimuli-triggered drug release and active targeting of tumors signify a dual smart strategy in chemotherapeutic inhibition of cancer growth. Recently, low molecular weight protamine (Prt_LMW) has been utilized to replace its precursor protamine (Prt) in the clinic, as it exhibits less undesirable side effects. In this study, we compared the merits of using Prt and Prt_LMW to assemble two NPs. Anticancer drug doxorubicin (Dox) was loaded into ATP-binding aptamer (Apt_ATP), a DNA sequence that undergoes a conformational change when exposed to an Adenosine-5′-triphosphate (ATP) rich environment. Dox-Apt_ATP then complexed with the positively charged Prt or Prt_LMW, and the resulting cationic, condensed core was further coated with high molecular weight hyaluronic acid (HA_HMW), a known ligand for tumor marker CD44. The resulting two NPs were characterized then …​