Intrathecal Delivery of Macromolecules to the Spinal Cord Enabled by Laser-Activated Perfluorocarbon Nanodroplets.

The lack of safe, minimally invasive strategies for targeted drug delivery to the spinal cord remains a major barrier to treating neurodegenerative disease and spinal injury. Intrathecally administered macromolecules, including gene therapy vectors, rarely penetrate spinal tissue at therapeutically relevant concentrations due to cellular barriers at the cerebrospinal fluid-spinal cord interface. Here, we demonstrate the application of laser-activated perfluorocarbon nanodroplets (PFCnDs) for nonsurgical, spatially controlled delivery from the subarachnoid space into spinal cord parenchyma. Following intrathecal injection in rats, transdermal laser irradiation produced a 7-fold increase in photoacoustic signal within the spinal cord parenchyma compared to nonirradiated controls, confirming spatially selective intraparenchymal nanodroplet delivery. Codelivery of 500 kDa FITC-dextran demonstrated approximately 1 mm penetration into the dorsal horn at irradiated sites, while nonirradiated regions showed only superficial perivascular accumulation. Neither nanodroplets alone nor laser irradiation alone produced intraparenchymal delivery, indicating that vaporization-induced cavitation is necessary for penetration. The PFCnDs (∼300 nm diameter) were engineered with a lipid shell, perfluorohexane core, and near-infrared absorbing dye for transdermal activation at 1064 nm. These results demonstrate that laser-activated nanodroplets can deliver macromolecular cargo into the spinal cord via lumbar puncture and transdermal irradiation, without surgical exposure.