<p>High-risk neuroblastoma poses significant therapeutic challenges due to tumor heterogeneity, drug resistance, and systemic toxicity associated with conventional chemotherapies. To overcome these limitations, we developed cyclic RGD-decorated solid lipid nanoparticles for integrin-targeted delivery of etoposide, aiming to enhance tumor selectivity and therapeutic efficacy. SLNs were prepared using hot homogenization and ultrasonication, with cyclic RGD peptides conjugated to the surface via non-covalent and covalent strategies. Among three conjugation approaches evaluated, maleimide-based functionalization was selected for its reproducibility, stability, and high coupling efficiency. RGD-functionalized SLNs were physicochemically characterized and assessed for integrin-mediated uptake, cytotoxicity, cell cycle effects, and apoptosis induction in SH-SY5Y (integrin-high) and SK-N-BE(2) (integrin-low) NB cell lines. RGD-SLNs demonstrated efficient peptide conjugation while maintaining colloidal stability and drug loading. Flow cytometry confirmed enhanced uptake in αvβ3 integrin-expressing SH-SY5Y cells, with moderate uptake in SK-N-BE(2) cells. ETP encapsulation within SLNs significantly improved its cytotoxic profile, with RGD functionalization further reducing IC₅₀ values and promoting apoptosis. These findings establish RGD-functionalized SLNs as a promising integrin-targeted platform for ETP delivery in NB. To our knowledge, this is the first report of this approach using SLNs for NB, offering a novel strategy for translational nanomedicine.</p> Graphical abstract <p></p>