Multifunctional silver nanoclusters with hyaluronic acid for dual-targeted tumor imaging and ROS-mediated therapy.

Despite their potential in cancer theranostics, silver nanoparticles (Ag NPs) face significant clinical translation challenges, including polydispersity, weak fluorescence emission, and suboptimal biocompatibility. To overcome these challenges, we introduce Ag@PEG2000-HA nanoclusters (NCs), novel silver-based NCs developed through a sequential functionalization process using polyethylene glycol (PEG) and hyaluronic acid (HA). The HA-induced stabilization enlarges nanocluster cores and promotes ligand-metal charge transfer, synergizing with size-dependent aggregation-induced emission (AIE) effect to amplify fluorescence. These developed nanoconstructs showcase enhanced theranostic capabilities, featuring strong near-infrared (NIR) fluorescence for live tumor imaging and reactive oxygen species (ROS)-enabled mitochondrial targeting to induce cancer cell apoptosis selectively. Systematic evaluations, both in vitro and in vivo, confirmed significant tumor growth inhibition, increased survival rates, and a positive biosafety profile. The dual-targeting approach, leveraging the enhanced permeability and retention (EPR) effect alongside HA-mediated CD44 interaction, ensures precise tumor targeting and reduces off-target effects. Additionally, the nanoclusters showed exceptional stability, extended blood circulation, and resistance to macrophage phagocytosis, thereby enhancing their therapeutic effectiveness. Detailed mechanistic studies showed that Ag@PEG2000-HA NCs trigger apoptosis via ROS production and mitochondrial disruption, and concurrently reduce the expression of key tumor-associated proteins (CD31, Ki-67, and MMP9), inhibiting angiogenesis, proliferation, and metastasis. This research establishes a multifunctional nanoplatform bridging diagnostic imaging and therapy, opening new avenues for precision oncology. The findings provide fundamental insights into the design principles of cluster-based theranostic nanomaterials, paving the way for their clinical translation in cancer treatment.