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Graphical abstract We engineered biodegradable DNA-loaded brain-penetrating nanoparticles (DNA-BPN) possessing small particle diameters ( less then  70 nm) and non-adhesive surface coatings to facilitate their spread through brain tumor extracellular matrix (ECM). These DNA-BPN provide widespread gene transfer in models recapitulating the ECM barrier, including three-dimensional multicellular tumor spheroids and mice with orthotopically established brain tumor.Recent research has been successful in demonstrating the importance of the addit