Synergistic Gene Immunotherapy for Lung Cancer via Targeted Nanomedicine Restoring Genetic Tumor Suppression and Activating STING Pathway.

Lung cancer, particularly non-small cell lung cancer (NSCLC), presents significant therapeutic challenges due to its high mortality and complex pathogenesis. General strategies, including chemotherapy, immunotherapy, and even novel gene therapy, fail to provide comprehensive inhibition against NSCLC individually. Here, a novel gene-immunotherapeutic nanomedicine, pTMEM163/cGAMP@cRGD-BSA/LDHs (TGR-BLDHs), was developed by employing cyclic Arg-Gly-Asp (cRGD)-modified bovine serum albumin/layered double hydroxide (BSA-LDH) nanoparticles for targeted delivery of TMEM163, a newly identified tumor suppressor gene (TSG) of NSCLC and cGAS/STING agonist (cGAMP). TGR-BLDHs exhibited highly specific NSCLC tumor suppression via desirable tumor-targeted TSG gene therapy. Meanwhile, TGR-BLDHs successfully evoked potent antitumor effects by activating the cGAS/STING pathway in both antigen-presenting and cancerous cells, eventually inhibiting tumor progression in vivo. The current study highlighted the potential of TGR-BLDHs for effective gene immunotherapy against NSCLC with desirable tumor specificity and biocompatibility, offering a promising gene-immunotherapeutic strategy for NSCLC.