Precisely Targeted Nano‐Controller of PD‐L1 Level for Non‐Small Cell Lung Cancer Spinal Metastasis Immunotherapy

Abstract Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non‐small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC‐SM), are insensitive to anti‐programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) ICIs. A drug delivery nano‐controller of PD‐L1 that targets NSCLC‐SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin β 3 ( β 3‐int) is strongly upregulated in NSCLC‐SM. Its inhibitor RGDyK promotes PD‐L1 ubiquitination, indicating the potential application of RGDyK as a new PD‐L1 inhibitor in nano‐controller and a targeting peptide for NSCLC‐SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T‐cell activation through the release of tumor antigens, RGDyK‐modified and zinc protoporphyrin (ZnPP)‐loaded mesoporous silicon nanoparticles (ZnPP@MSN‐RGDyK) are fabricated. The ZnPP@MSN‐RGDyK nanoparticles precisely target β 3‐int to inhibit PD‐L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC‐SM mouse model. Collectively, the findings indicate that ZnPP@MSN‐RGDyK is a promising immunotherapeutic agent for treating NSCLC‐SM.