Non-adhesive and highly stable biodegradable nanoparticles that provide widespread and safe transgene expression in orthotopic brain tumors.

Several generations of poly(β-amino ester) (PBAE) polymers have been developed for efficient cellular transfection. However, PBAE-based gene vectors, similar to other cationic materials, cannot readily provide widespread gene transfer in the brain due to adhesive interactions with the extracellular matrix (ECM). We thus engineered eight vector candidates using previously identified lead PBAE polymer variants but endowed them with non-adhesive surface coatings to facilitate their spread through brain ECM. Specifically, we screened for the ability to provide widespread gene transfer in tumor spheroids and healthy mouse brains. We then confirmed that a lead formulation provided widespread transgene expression in orthotopically established brain tumor models with an excellent in vivo safety profile. Lastly, we developed a method to store it long-term while fully retaining its brain-penetrating property. This new platform provides a broad utility in evaluating novel genetic targets for gene therapy of brain tumors and neurological disorders in preclinical and clinical settings. Graphical abstract We engineered biodegradable DNA-loaded brain-penetrating nanoparticles (DNA-BPN) possessing small particle diameters (< 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.