Targeting neuroinflammation and PVNCRH neurons: dexmedetomidine liposomes for perioperative neurocognitive disorder with comorbid anxiety

Perioperative neurocognitive disorder (PND) and anxiety are major perioperative complications that are typically managed independently, despite their frequent co-occurrence and mutual exacerbation. However, treatments for each condition have drawbacks, and no effective dual therapy exists. Here, a brain-targeted liposomal formulation (D@ACLipo) was developed for the co-delivery of the perioperative sedative dexmedetomidine (DEX) and the microglia-modulating peptide COG1410, incorporating Angiopep-2 to enhance brain penetration. In the PND mouse model, D@ACLipo pretreatment provided dual benefits, significantly alleviating surgery-induced cognitive impairment and anxiety-like behaviors with superior efficacy. As neuroinflammation is a pivotal driver of PND, mechanistic studies revealed that DEX modestly attenuated it via toll-like receptor 4 (TLR4) inhibition, whereas COG1410 further amplified anti-inflammatory responses by upregulating triggering receptor expressed on myeloid cells-2 (TREM2). Additionally, <i>in vivo</i> fiber photometry revealed that DEX significantly suppressed corticotropin-releasing hormone (CRH) neuron activity in the paraventricular nucleus (PVN), contributing to its anxiolytic effect. These findings highlight a promising translational nanotherapeutic strategy for the dual prevention of PND and anxiety by targeting molecular signaling pathways and neural circuits.