Tripolyphosphate-crosslinked chitosan (TPPCS) nanoparticles were employed in the encapsulation of lenalidomide (LND) using a straightforward ionic cross-linking approach. The primary objectives of this technique were to enhance the bioavailability of LND and mitigate inadequate or overloading of hydrophobic and sparingly soluble drug towards cancer cells. In this context, a quantum chemical model was employed to elucidate the characteristics of TPPCS nanoparticles, aiming to assess the efficiency of these nanocarriers for the anticancer drug LND. Fifteen configurations of TPPCS and LND (TPPCS /LND1-15) were optimized using B3LYP density functional level of theory and PCM model (H2O). AIM analysis revealed that the high drug loading capacity of TPPCS can be attributed to hydrogen bonds, as supported by the average binding energy (168 kJ mol−1). The encouraging theoretical results prompted us to fabricate this drug delivery system and characterize it using advanced analytical techniques. The encapsulation efficiency of LND within the TPPCS was remarkably high, reaching approximately 87 %. Cytotoxicity studies showed that TPPCS/LND nanoparticles are more effective than the LND drug. To sum up, TPPCS/LND nanoparticles improved bioavailability of poorly soluble LND through cancerous cell membrane. In light of this accomplishment, the novel drug delivery route enhances efficiency, allowing for lower therapy doses.