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

## TL;DR

A new hydrogel system delivers estradiol to brain astrocytes, reducing depression in perimenopausal mice by inhibiting a specific receptor pathway.

## Contribution

A biomimetic nanoliposome hydrogel for targeted estradiol delivery to astrocytes, improving perimenopausal depression via P2X7 receptor inhibition.

## Key findings

- AEC@CP delivery system effectively targets astrocytes and reduces hippocampal pyroptosis in perimenopausal mice.
- Estradiol inhibits the P2X7R/NLRP3/caspase-1/GSDMD pathway, reducing inflammatory markers like IL-18 and IL-1β.
- AEC@CP showed stronger antidepressant and anti-pyroptotic effects compared to free estradiol.

## Abstract

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.