Microneedle-mediated delivery of Ziconotide-loaded liposomes fused with exosomes for analgesia

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid , intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury , diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain . BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95  nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC.