Target anesthesia and surgery induced senescent cell via composite microsphere hydrogels as nose-to-brain amplifiers of platelet factor 4 delivery for neurocognitive dysfunction repair.

Perioperative neurocognitive disorder (PND) is a common complication in older surgical patients, leading to increased neurodegenerative and death risk, augment socioeconomic burdens. Despite its prevalence, the reasons of why this complication occurs highly in older, underlying pathogenesis mechanisms, and effective treatments remain unclear. Senescence associated secretory phenotype (SASP), resulting from cellular senescence, drives inflammaging and cognitive decline. However, the association between cellular senescent and poor cognitive outcome is seldomly defined in PND. Herein, we showed that anesthesia and surgery in aged mice further increase hippocampal neuron senescent burden, manifest as increased senescence-like markers (CDKN2A/p16, CDKN1A/p21, SASP, SA-β-Gal), along with lipofuscin and lipid droplet accumulation and synaptic dysfunction. We identified elevated PF4, a platelet-derived factor, as a defensive response in older PND mice. Intraperitoneal PF4 administration mitigated neuronal senescence burden and improved cognitive dysfunction. Considering the older, frail patients and shorter perioperative period, we developed microfluidic hydrogel microspheres and cationic thermosensitive hydrogel complexes for nasal PF4 delivery enabling satisfy minimally invasive, less frequent dosing and sustained treatment. These findings reveal a critical role for cellular senescence in PND and propose PF4-based therapies as a promising translational strategy.