Baclofen-functionalized glycogen nanoparticles for GABAB receptor-mediated lung cancer cell-targeted delivery of survivin ASO

As an inhibitor of apoptosis protein, survivin attracts growing interest as a oncotarget because it is highly expressed in various cancers but lacks expression in normal tissues. Although silencing survivin mRNA using antisense oligonucleotides (ASO) presents a potential strategy for lung cancer treatment, the application of ASO is constrained by multiple barriers, including rapid enzymatic degradation, limited cellular internalization and non-specific tissue distribution. To overcome these challenges, we engineered a novel glyco-nanocarrier by chemically modifying glycogen. Glycogen was aminated (NG) and further conjugated with baclofen (Bac-NG), a ligand and agonist for GABAB receptors overexpressed in lung cancer cells. Bac-NG demonstrated excellent biocompatibility and efficiently complexed with survivin ASO through electrostatic interactions, protecting it from nuclease degradation. Bac-NG significantly improved the internalization of ASO in A549 cells via GABAB receptor-mediated endocytosis. Consequently, Bac-NG/ASO effectively inhibited A549 cell proliferation by triggering apoptosis. This study highlights the therapeutic promise of Bac-NG/ASO for targeted gene therapy in lung cancer