This work provides insights over a novel biodegradable polymeric nanosystem made of hyaluronic acid and polyarginine for diaminocyclohexane-platinum (DACHPt) encapsulation. Using mild conditions based on ionic gelation technique, monodispersed blank and DACHPt-loaded nanoparticles (NP) with a size of around 200 nm and negative ζ potential (-35 mV) were obtained. The freeze-drying process was optimized to improve the stability and shelf-life of the developed nanoparticles. After reconstitution, nanoparticles maintained their size showing an association efficiency of around 70 % and a high drug loading (8%). In vitro cytotoxicity studies revealed that DACHPt-loaded nanoparticles had a superior anticancer activity compared with oxaliplatin solution. The IC50 was reduced by a factor of two in HT-29 cells (IC50 39 µM vs 74 µM, respectively), and resulted almost 1.3 fold lower in B6KPC3 cells (18µM vs 23µM respectively). Whereas toxic effects of both drug and DACHPt-loaded nanoparticles were comparable in the A549 cell line (IC50 11 µM vs 12 µM). DACHPt-loaded nanoparticles were also able to modulate immunogenic cell death (ICD) in vitro. After incubation with B6KPC3 cells, an increase in HMGB1 (high-mobility group box 1) production associated with ATP release occurred. Then, in vivo pharmacokinetic studies were performed after intravenous injection (IV) of DACHPt-loaded nanoparticles and oxaliplatin solution in healthy mice (35.9 µg of platinum equivalent/mouse). An AUC six times higher (24 h*mg/L) than the value obtained following the administration of oxaliplatin solution (3.76 h*mg/L) was found. Cmax was almost five times higher than the control (11.4 mg/L for NP vs 2.48 mg/L). Moreover, the reduction in volume of distribution and clearance clearly indicated a more limited tissue distribution. A simulated repeated IV regimen was performed in silico and showed no accumulation of platinum from the nanoparticles. Overall, the proposed approach discloses a novel nano-oncological treatment based on platinum derivative with improved antitumor activity in vitro and in vivo stability as compared to the free drug.