Gold-incorporated hyaluronic acid nanoparticles enhance ablative radiotherapy efficacy in lung cancer

We aimed to investigate the utility of Au-incorporated hyaluronic acid nanoparticles (Au/HA NPs) for improving the therapeutic efficacy of ablative radiotherapy (RT) for tumor control and microenvironment remodeling. HA-functionalized NPs exhibited uniform size, stability, and efficient SN38 encapsulation. Au incorporation increased NP diameter and reduced surface charge while remaining stable. HA and Au/HA NPs were efficiently internalized by lung cancer cells, with free HA pretreatment suppressing internalization. Moreover, Au/HA NP internalization strongly downregulated CD44 expression in lung cancer cells, confirming CD44-mediated internalization. <i>In vitro</i>, Au/HA NPs enhanced radiation-induced G2/M phase arrest and γH2AX foci formation with increased DNA double-strand breaks. Au/HA NPs and RT induced immunogenic cell death (ICD) in lung cancer cells, characterized by elevated reactive oxygen species, increased calreticulin surface expression, and extracellular adenosine triphosphate release. Tumor control, survival, immune infiltration, and systemic effects were investigated <i>in vivo</i> using A549 xenografts and Lewis lung carcinoma synchronous flank-lung tumor models. Au/HA NPs and ablative RT decreased tumor growth, reduced lung tumor burden in non-irradiated areas, and prolonged survival. This therapeutic combination led to increased infiltration of natural killer (NK), NK T, CD8⁺ T, and dendritic cells and decreased regulatory T cells, suggesting robust immunological activation. Biodistribution studies confirmed CD44-targeted tumor-specific NP accumulation. No substantial toxicity was observed. In conclusion, Au/HA NPs and ablative RT induced ICD <i>in vivo</i>. Au/HA NPs enhanced local and systemic immunity <i>via</i> radiosensitization and ICD. This NP-assisted approach may improve RT efficacy in lung cancer.