A Multistage‐Responsive Antibody‐Delivery Strategy to Improve Immunotherapy for NSCLC Brain Metastasis by Ultrasensitive Releasing and Tumor‐Anchoring

Abstract Immune checkpoint blockade (ICB) therapy has emerged as a promising approach in clinical oncology. For brain metastases, the presence of the robust blood–brain barrier (BBB) and potential immune‐related adverse events (irAEs) pose significant challenges. Here, a multistage‐responsive antibody‐delivery strategy is developed for non‐small cell lung cancer (NSCLC) brain metastases, with the ultra‐pH sensitivity borate bonds. The antibody‐delivery nanoformulation (MB‐aPDL1) is able to maintain the “silent state” in health tissue, cross the BBB/BTB by the GLUT1‐mediated transcytosis, release the functionalized aPDL1 responsively, and promote the aPDL1 tumor‐anchoring. In the in vivo tumor region, the MB‐aPDL1 rapidly releases the activated BPA 6 ‐aPDL1, which successfully anchors to the tumor cells and improves the efficiency of ICB therapy. The two in vivo ICB therapy studies show a significant tumor growth inhibition from the MB‐aPDL1 with an encouraging cure rate of 20% for the NSCLC brain metastases, due to enhanced immune response in tumor, commendably with less behavioral adverse reactions and liver damage. Taken together, this antibody‐delivery strategy holds substantial potential for application in clinical treatment of brain metastases.