Bioengineered Carboxymethyl Cellulose-Based Immunoconjugates Templating Cobalt-Substituted Iron Oxide Nanoparticles for Targeted Enzyodynamic-Enabled Ferroptosis and Photothermal Therapy of Glioblastoma

Regrettably, glioblastoma multiforme (GBM) remains incurable due to aggressiveness and recurrence driven by cancer stem-like cells, where CD44 cell-surface receptors are highly overexpressed. Hence, in this research, the development, synthesis, and extensive characterization of novel bioengineered hybrid immunoconjugates for targeted multimodal therapy of GBM are reported. These organic–inorganic nanohybrids were designed to form colloidal nanostructures using an anionic carboxymethyl cellulose (CMC) polysaccharide as a templating biomacromolecule for the nucleation and stabilization of a cobalt-substituted iron oxide nanoparticle (Co0.4-Fe2.6O4), which exhibits peroxidase-mimicking nanocatalytic activity (POD-like) and optical photothermal conversion for anticancer therapy. They were biofunctionalized by coupling anti-CD44 antibodies to CMC (CMC-abCD44) for immunotargeting GBM cells. The results demonstrated that colloidal nanoarchitectures were formed by polysaccharide-antibody bioconjugate layers surrounding inorganic Co-substituted magnetite nanoparticles (Co0.4-Fe2.6O4, spherical morphology, diameter = 5.7 nm; Co0.4-Fe2.6O4@CMC-abCD44, zeta potential of −56 mV and hydrodynamic diameter = 73 nm). These immunoconjugates induced selective, targeted CD44 receptor-specific GBM cell death via a multimodal mechanism involving biocatalytic enzyodynamic-enabled ferroptosis (EDT) combined with near-infrared (NIR)-responsive photothermal therapy (PTT) in 2D and 3D gliomasphere cell models. This dual EDT/PTT strategy effectively eliminates GBM cells and provides an immunotarget-driven, multimodal GBM therapy framework, offering a promising translational path for glioblastoma management.