Background <p>Advances in nanomedicine have spurred interest in antibody-conjugated carbon nanotubes for targeted cancer therapy. CD133, a marker enriched in chemoresistant cancer stem cells, presents a strategic target for precision drug delivery. This study explores functionalized single-walled carbon nanotubes (SWCNTs) as dual-action platforms for enhanced doxorubicin (DXR) delivery and CD133-specific targeting.</p> Methods <p>Two nano formulations-SWCNT-Ab/DXR (antibody-functionalized) and SWCNT-PEG-Ab/DXR (pegylated antibody-functionalized)-were engineered to encapsulate DXR. Release profiles, cytotoxicity, and apoptosis were assessed in CD133⁺ HT-29 colorectal cancer cells and CD133⁻ CHO control cells. Computational modeling included DFT-D structural optimization, Monte Carlo adsorption simulations for DXR binding analysis, and molecular docking to evaluate carrier-receptor interactions.</p> Results <p>PEGylation markedly enhanced colloidal stability and drug-loading capacity, with SWCNT-PEG-Ab/DXR achieving 92% DXR encapsulation vs. 78% for non-PEGylated counterparts. In vitro, the PEGylated system showed amplified cytotoxicity (IC50: 2.1 µM vs. 3.8 µM for SWCNT-Ab/DXR) and 1.7-fold higher apoptosis induction in HT-29 cells. Computational data aligned with experimental findings: DXR adsorption energy was strongest on PEG-NH₂-modified SWCNTs (− 32.6&#xa0;kcal/mol) versus carboxylated variants (− 24.8&#xa0;kcal/mol), confirming PEG’s role in stabilizing drug-carrier interactions.</p> Conclusions <p>By integrating PEG-mediated stealth properties, charge-modified surfaces, and antibody targeting, SWCNT-PEG-Ab/DXR emerges as a multifunctional nanoplatform with enhanced tumor selectivity and therapeutic payload delivery. This dual experimental-computational approach underscores the potential of rationally engineered nanotubes to overcome limitations in conventional chemotherapy.</p> Graphical Abstract <p></p>