Abstract Glioblastoma multiforme (or GBM) remains one of the deadliest types of brain cancers. Nanomedicine can offer new strategies for fighting against GBM by combining the earliest possible diagnosis with multiple options of therapy. Hence, in this work, cysteine (Cys) and Poly-L-Arginine (PA) moieties were grafted to carboxymethyl cellulose (CMC) to produce biofunctional hybridized macromolecules (CMC_Cys and CMC_PA). These polymer-peptide conjugates were used simultaneously as surface capping ligands and biofunctional modifiers for the synthesis of ternary Ag-In-S (AIS) quantum dots (AIS QDs) via a green chemical process in aqueous medium and room temperature. These core-shell supramolecular nanostructures (AIS@CMC, AIS@CMC_Cys, and AIS@CMC_PA) were tested as fluorescent nanoprobes (“OFF-ON”) for targeted bioimaging and in vitro intracellular tracking of glioblastoma cells (GBM, U-87 MG). The nanosystems were characterized for physicochemical, structural, and morphological properties by NMR, UV–Vis, PL, FTIR, TEM/EDX/SAED, zeta potential, and DLS. Cytocompatibility was evaluated by mitochondrial activity assay, and confocal laser scanning microscopy was performed for investigating the kinetics of cellular uptake. The grafting caused a noticeable reduction of surface charges, associated with a drastic photoluminescence quenching (i.e., “OFF-state”) of AIS@CMC_Cys and AIS@CMC_PA compared to unmodified AIS@CMC. This effect was smartly applied for bioimaging GBM cells and for monitoring the internalization process by intracellular tracking, which underwent strong “de-quenching” at very early incubation times (~5 min). Thus, these novel hybrid nanocolloids produced via eco-friendly scalable aqueous process show potential as responsive fluorescent bioprobes for bioimaging and tracking intracellular pathways and mechanisms as a powerful weapon for fighting against brain cancer cells.