Engineered peptide-oligonucleotide composite nanotubes for redox-triggered drug delivery in cellular and pre-clinical glioma models.

Peptide-oligonucleotide complexes (POCs) represent a promising platform in targeted therapeutics, offering potential for drug delivery and gene therapy in complex diseases. This study focuses on the design, characterization, and anticancer application of doxorubicin (Dox)-loaded POCs for glioma treatment. The complexes were synthesized using glutathione (GSH) and an 18-mer oligonucleotide, exploiting the elevated enzymatic activity in cancer cells for targeted delivery. By encapsulating Dox within POCs, the system addresses the limitations of conventional Dox therapy, including non-specific distribution and cardiotoxicity, while enhancing uptake by glioma cells. In vitro studies demonstrated that Dox-loaded POCs achieved high intracellular retention and induced marked cytotoxicity against glioma cells. The primary mechanism involved the generation of reactive oxygen species (ROS), that caused DNA double-strand breaks triggering apoptosis. In vivo evaluation using ectopic glioma models demonstrated notable therapeutic efficacy, resulting in approximately 70 % reduction in tumor mass. Histopathological and immunohistochemical analyses further confirmed their antitumor action. NF-κB p-65 nuclear translocation was reduced by ∼60 %, indicating suppression of pro-survival and inflammatory pathways. The Ki-67 proliferation index decreased by ∼76 %, signifying substantial inhibition of tumor cell replication. These biomarkers are typically overexpressed in gliomas, contributing to therapy resistance and the uncontrolled growth of tumors. The findings reveal that Dox-loaded POCs operate via a multimodal mechanism, targeted delivery, oxidative stress induction, DNA damage, and suppression of proliferative and survival signaling. This integrated approach enhances therapeutic specificity while minimizing systemic toxicity, positioning POCs as strong candidates for advanced translational therapies for glioma.