Ischemic stroke is still the major cause of disability worldwide. Although
vascular endothelial growth factor (
VEGF) is able to promote both angiogenesis and functional recovery, its use is limited by needle-induced injury, nonhomogenous
VEGF distribution, and limited
VEGF retention in the brain after intracranial or
intravenous injection. Here, we first present a
gelatin methacryloyl (GelMA) microneedle (MN)-based platform for the sustained and controlled local delivery of an adeno-associated virus (AAV) expressing human
VEGF (AAV-
VEGF) that achieves homogenous distribution and high transfection efficiency in ischemic brains. An
ischemic stroke model was established in adult rats, and MNs loaded with AAV-
VEGF were epicortically inserted into both the ischemic core and penumbra of these rats one day after the onset of
ischemia. One week later, the inflammatory response and microneedle biocompatibility were assessed by
enzyme-linked
immunosorbent assay (ELISA) and immunofluorescence. Eight weeks later, angiogenesis and neural stem cell proliferation and migration were assessed. GelMA MN implantation did not elicit an obvious inflammatory response and had good biocompatibility in the brain. AAV-
green fluorescent protein (GFP)-loaded MNs could achieve successful transfection and homogeneous distribution in the brain cortex three weeks postoperatively. MNs loaded with AAV-
VEGF increased
VEGF expression and enhanced functional angiogenesis and neurogenesis. In summary, MNs might emerge as a promising platform for delivering various
therapeutics to treat
ischemic stroke and repair other neurologically diseased tissues.