Convection-enhanced delivery of nanoencapsulated gene locoregionally yielding ErbB2/Her2-specific CAR-macrophages for brainstem glioma immunotherapy

Locoregional delivery of chimeric antigen receptor (CAR)-modified T (CAR-T) cells has emerged as a promising strategy for brain tumors. However, the complicated ex vivo cell manufacturing procedures and the rapid progression of the disease have limited its broader applications. Macrophages (M phi s) exhibit unique effector functions and a high degree of infiltration within the solid tumor microenvironment (TME), especially in the brain, where M phi s function as structural support, and the main immune effector cells of the CNS represent 5-12% of brain cells. Here, we report a synthetic universal DNA nanocarrier for in situ genetic editing of intratumoral M phi s with an ErbB2-specific CAR to direct their phagocytic activity towards tumors and subsequently initiate a locoregional antitumor immune response. Specifically, we demonstrated that when delivered locoregionally, the RP-182 peptide, located in the shell of a nanoparticle, targeted M phi s and reprogrammed M2-like tumor-associated macrophages (TAMs) to an antitumor M1-like phenotype. Subsequently, the CAR gene-laden DNA nanocomplex can be used to introduce ErbB2-targeted CAR, and the generated CAR-M phi s then act as living cures, thereby serially clearing the invasive tumor cells. Our work demonstrates a practical antitumor immunotherapy for brainstem gliomas (BSGs) that may be broadly applicable for patients suffering from other ErbB2-positive solid malignancies.

Automated summary

A synthetic universal DNA nanocarrier was developed for in situ genetic editing of macrophages (M phi s) within brain tumors, which directed their phagocytic activity towards tumors and initiated an antitumor immune response. This approach could potentially be applied to patients suffering from other ErbB2-positive solid malignancies, providing a practical antitumor immunotherapy for brainstem gliomas (BSGs).