Therapeutic peptides have emerged as promising tools in oncology due to their high specificity, favorable safety profile, and capacity to target molecular hallmarks of cancer. Their clinical translation, however, remains limited by poor stability, rapid proteolytic degradation, and inefficient biodistribution. Iron oxide nanoparticles (IONPs) offer a compelling solution to these challenges. Owing to their biocompatibility, magnetic properties, and ability to serve as both drug carriers and imaging agents, IONPs have become a versatile platform for precision nanomedicine. The integration of peptides with IONPs has generated a new class of hybrid systems that combine the biological accuracy of peptide ligands with the multifunctionality of magnetic nanomaterials. Peptide functionalization enables selective tumor targeting and deeper tissue penetration, while the IONP core supports controlled delivery, MRI-based tracking, and activation of therapeutic mechanisms such as magnetic hyperthermia. These hybrids also influence the tumor microenvironment (TME), facilitating stromal remodeling and improved drug accessibility. Importantly, the iron-driven redox chemistry inherent to IONPs can trigger regulated cell death pathways, including ferroptosis and autophagy, inhibiting opportunities to overcome resistance in aggressive or refractory tumors. As advances in peptide engineering, nanotechnology, and artificial intelligence accelerate design and optimization, peptide–IONP conjugates are poised for translational progress. Their combined targeting precision, imaging capability, and therapeutic versatility position them as promising candidates for next-generation cancer theranostics.

An amphiphilic copolymer of N-vinyl-2-pyrrolidone and acrylic acid—namely, p(VP-AA)-OD6000 (p(VP-AA))—was synthesized to prepare p(VP-AA) nanoparticles (NPs). Furthermore, the copolymer was linked with CFSE, and the so-prepared nanoparticles were loaded with the DiI dye to form D nanoparticles (DNPs). In this study, as demonstrated by immunofluorescence microscopy, immunofluorescence, and confocal microscopy, DNPs were readily taken up by human microvascular endothelial cells (HMEC-1) cells in a concentration-dependent manner. Upon uptake, both the CFSE dye (green stain) and the DiI dye (red stain) were localized to the cytoplasm of treated cells. Treatment with p(VP-AA) did not affect the viability of normal and challenged with LPS, HMEC-1 cells at 0.010 mg/mL and induced a dose-dependent decrease of these cells’ viability at the higher concentrations of 0.033 and 0.066 mg/mL (p ≤ 0.01; p ≤ 0.001, respectively). Furthermore, we focused on the potential immunological activation of HMEC-1 endothelial cells upon p(VP-AA) NPs treatment by assessing the expression of adhesion molecules (E-Selectin, ICAM-1, and V-CAM). NPs treatments at concentrations utilized (p = NS) did not affect individual adhesion molecules’ expression. p(VP-AA) NPs do not activate the endothelium and do not affect its viability at pharmacologically relevant concentrations.