A novel antibody-conjugated drug-loaded nanoparticle (ADN) platform combining immunotherapy and molecularly targeted therapy has been developed for the treatment of non-small cell lung cancer (NSCLC). The ADN consists of anti-CD47 and anti-PDL1 antibodies on the nanoparticle surface and the PI3K/AKT/mTOR inhibitor PI103 inside. This dual-targeting approach enhances both innate and adaptive immunity while inhibiting oncogenic pathways. The ADN showed improved antitumor efficacy compared to existing therapies in an aggressive NSCLC mouse model. CD47 and PDL1 are overexpressed in NSCLC, and their inhibition can enhance immune cell activity. The ADN effectively binds to these immune checkpoints, increases phagocytosis of cancer cells by macrophages, and reduces tumor growth. In vivo studies in immunocompetent mice showed that the ADN significantly reduced tumor size and improved survival rates compared to single-agent immunotherapy. The ADN also demonstrated reduced toxicity to normal cells and showed no significant adverse effects. The ADN platform offers a promising approach for NSCLC treatment by targeting multiple immune checkpoints and inhibiting oncogenic pathways.A novel antibody-conjugated drug-loaded nanoparticle (ADN) platform combining immunotherapy and molecularly targeted therapy has been developed for the treatment of non-small cell lung cancer (NSCLC). The ADN consists of anti-CD47 and anti-PDL1 antibodies on the nanoparticle surface and the PI3K/AKT/mTOR inhibitor PI103 inside. This dual-targeting approach enhances both innate and adaptive immunity while inhibiting oncogenic pathways. The ADN showed improved antitumor efficacy compared to existing therapies in an aggressive NSCLC mouse model. CD47 and PDL1 are overexpressed in NSCLC, and their inhibition can enhance immune cell activity. The ADN effectively binds to these immune checkpoints, increases phagocytosis of cancer cells by macrophages, and reduces tumor growth. In vivo studies in immunocompetent mice showed that the ADN significantly reduced tumor size and improved survival rates compared to single-agent immunotherapy. The ADN also demonstrated reduced toxicity to normal cells and showed no significant adverse effects. The ADN platform offers a promising approach for NSCLC treatment by targeting multiple immune checkpoints and inhibiting oncogenic pathways.