Gold nanoparticles (GNPs) are promising radiosensitizers owing to their high atomic number, but their therapeutic efficacy is often limited by reticuloendothelial system (RES)-mediated clearance and poor tumor accumulation attributable to elevated interstitial fluid pressure. This study explored macrophage-mediated GNP delivery to enhance radiotherapy (RT) efficacy in oral cancer by leveraging the tumor-homing ability, immune plasticity, hypoxia tropism, and RES evasiveness of macrophages. Murine oral cancer cells (MCTQ1) and macrophages (RAW 264.7) were used. GNPs were synthesized using the Turkevich method, which were then assessed for radiosensitization using cell viability and colony formation assays. GNPs were radiolabeled with Iodine-131 (131I) using the chloramine-T method, and uptake by RAW 264.7 cells was quantified at various time points to optimize the generation of GNP-loaded macrophages (GNP@Rs). MTCQ1 tumor-bearing mice were divided into control, RT, GNP, RAW, GNP + RT, RAW + RT, and GNP@R + RT groups. Tumor volumes were monitored after GNP or cell administration and/or RT (8 Gy). Flow cytometry was used to analyze the immune cell populations post-treatment. Transwell assays confirmed that GNP loading did not impair macrophage migration, and in vivo fluorescence imaging demonstrated strong tumor tropism of RAW 264.7 cells and GNP@Rs. GNP@Rs maintained their migration ability and exhibited robust tumor accumulation for up to 96 h. Notably, GNP@R + RT treatment significantly enhanced tumor suppression relative to RT alone and increased the infiltration of macrophages, activated dendritic cells, CD4+ and CD8+ T cells, and natural killer cells. Macrophage-mediated GNP delivery successfully improved RT outcomes in oral cancer by increasing radiosensitivity and modulating immune microenvironment.
© 2025 The Authors. Published by Elsevier Ltd.

Various pathological characteristics of autism spectrum disorder (ASD) stem from abnormalities in brain resident immune cells, specifically microglia, to prune unnecessary synapses or neural connections during early development. Animal models of ASD exhibit an abundance of synapses in different brain regions, which is strongly linked to the appearance of ASD behaviors. Overexpression of CD47 on neurons acts as a "don't eat me" signal, safeguarding synapses from inappropriate pruning by microglia. Indeed, CD47 overexpression occurs in 16p11.2 deletion carriers, causing decreased synaptic phagocytosis and the manifestation of ASD characteristics. However, the role of CD47 in synaptic pruning impairment leading to ASD phenotypes in the 16p11.2 deletion mouse model is unclear. Moreover, whether blocking CD47 can alleviate ASD mice's behavioral deficits remains unknown. Here, we demonstrate a strong link between increased CD47 expression, decreased microglia phagocytosis capacity, and increased impairment in social novelty preference in the 16p11.2 deletion mice. The reduction in microglia phagocytosis caused a rise in excitatory synapses and transmission in the prefrontal cortex of 16p11.2 deletion mice. Importantly, blocking CD47 using a specific CD47 antibody or reducing CD47 expression using a specific short hairpin RNA (shRNA) enhanced the microglia phagocytosis and reduced excitatory transmission. Reduction in CD47 expression improved social novelty preference deficits in 16p11.2 mice. These findings demonstrate that CD47 is associated with the ASD phenotypes in the 16p11.2 deletion mice and could be a promising target for the development of treatment for ASD.

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients.