Glucose‐Facilitated Nanomicelles Cross Peripheral Nerve Barriers to Achieve Drug Delivery to Nerves

Injecting nerve-blocking agents near peripheral nerves is a clinical option for treating post-operative and chronic pain. However, the peripheral nerve barriers (PNBs) pose a physiological barrier that hinders the permeation of nerve-blocking agents through PNBs, ultimately affecting their efficacy on neurons. Here, glucose-modified nanomicelles (Glu-NMs) are developed that are self-assembled from glucose-functionalized 3-aminophenylboronic acid-polyethylene glycol- stearic acid polymer (GLU-PBA-PEG-SA) and Pluronic P₁₂₃. It is demonstrated that Glu-NMs exhibit enhanced cellular uptake by perineurial cells and improved permeation through PNBs in rats, compared to unmodified nanomicelles (NMs). This enhancement is facilitated by carrier-mediated transport through glucose transporters. A single injection of capsaicin-loaded Glu-NMs (CAP@Glu-NMs) containing 1 mg of capsaicin at the sciatic nerves of rats resulted in nociceptive-selective nerve blockade lasting for 48.0 ± 19.6 h, which is seven times longer than the duration achieved with an equivalent dose of plain capsaicin and twice as long as that of capsaicin-loaded NMs (CAP@NMs). Furthermore, the CAP@Glu-NMs significantly mitigate capsaicin-associated side effects and result in benign local tissue reactions.