Preclinical Evaluation of cRGD-Functionalized Lipid-Polymer Hybrid Nanocarriers for Anti-VEGF Gene Therapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes owing to its high metastatic potential and the absence of effective molecularly targeted therapies. Although cRGD-functionalized nanocarriers have been extensively investigated for TNBC treatment, most reported systems primarily deliver chemotherapeutic agents or short regulatory RNAs. In the present study, we developed and preclinically evaluated a cRGD-functionalized lipid-polymer hybrid gene delivery system (cRGD-LPH-GDS) specifically engineered for the delivery of therapeutic plasmid DNA (pDNA) targeting the VEGF/VEGFR2 signaling axis. The nanosystem was prepared by a self-assembly approach using DSPE-PEG-Maleimide and cyclic arginine-glycine-aspartic acid (cRGD), yielding nanoparticles with a mean hydrodynamic diameter of 19.40 ± 0.43 nm, a zeta potential of +22.8 ± 1.6 mV, and a polydispersity index of 0.25. The hybrid formulation demonstrated effective protection of pDNA against serum- and DNase I-mediated degradation while maintaining reversible cargo release under destabilizing conditions. In vitro studies demonstrated acceptable cytocompatibility, enhanced receptor-mediated cellular uptake, improved transfection efficiency, and significant suppression of VEGF-A expression in 4T1 cells. Competitive receptor-blocking experiments further confirmed the contribution of αvβ3 integrin-mediated targeting to the enhanced biological activity of the targeted formulation. In an orthotopic 4T1 BALB/c mouse model, intratumoral administration of cRGD-LPH-GDS:pDNA significantly inhibited tumor growth, reduced intratumoral VEGF-A expression, and prolonged survival without evident systemic toxicity. Collectively, these findings demonstrate that integration of a lipid-polymer hybrid structure with therapeutic plasmid DNA delivery and cRGD-mediated targeting provides an effective non-viral system for anti-angiogenic gene therapy. The developed nanosystem represents a promising foundation for the further preclinical development of targeted pDNA delivery strategies for TNBC.

Abstract from PubMed (PMID 42992543). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.