Bionic Nanoparticle Hydrogel for Astrocyte-Targeted Estradiol Delivery Ameliorates Perimenopausal Depression via P2X7 Receptor Inhibition

Estrogen (E2) therapy has shown efficacy in alleviating perimenopausal depression but is often accompanied by adverse effects when administered systemically. In this study, we developed a biomimetic nanoliposome hydrogel nasal delivery system for targeted E2 delivery and investigated its mechanisms. The system was constructed using aminated mesoporous silica as a carrier to load E2, followed by coating with astrocyte cell membranes to achieve targeting capability. The resulting nanoparticles were then embedded in a thermosensitive hydrogel composed of carboxymethyl chitosan and Pluronic F127, forming a nasal delivery platform (AEC@CP) for efficient brain targeting. A perimenopausal depression mouse model (OVX-CUMS) was established to evaluate E2's effects on depressive behavior, hippocampal pyroptosis, and the P2X7 receptor (P2X7R)/NLRP3/caspase-1/gasdermin (GSDMD) pathway. In vitro, primary astrocytes were induced with lipopolysaccharide-adenosine triphosphate to construct a P2X7R overexpression model. AEC@CP was characterized and tested for therapeutic efficacy both in vitro and in vivo. Results showed that OVX-CUMS mice exhibited elevated astrocytic pyroptosis, which was attenuated by E2. E2 down-regulated interleukin-18 (IL-18) and IL-1β in the hippocampus and inhibited P2X7R/NLRP3/caspase-1/GSDMD signaling. In vitro, E2 suppressed astrocytic pyroptosis and associated pathway activation, and P2X7R overexpression reversed these effects. AEC@CP demonstrated excellent targeting and cellular uptake, and exerted stronger antidepressant and anti-pyroptotic effects than did free E2. In conclusion, AEC@CP effectively delivers E2 to astrocytes, suppressing the P2X7R-mediated inflammasome pathway, reducing pyroptosis, and improving depressive behavior in perimenopausal mice.