Stability‐enhanced liposomal system co‐loaded with γ ‐aminobutyric acid and naringenin: outstanding sleep‐promoting efficacy

Abstract BACKGROUND Due to weak stability and bioavailability, γ ‐aminobutyric acid (GABA) and naringenin (Nar), two agents with sleep‐promoting activities, are limited in practical application. To improve their sleep‐promoting efficacy, this study developed a stability‐enhanced co‐loaded liposomal system (GABA‐Nar‐Lip) as a lyophilized powder. RESULTS The non‐lyophilized GABA‐Nar‐Lip exhibited good dispersibility, with an average particle size of 161.34 ± 1.68 nm, and achieved encapsulation efficiencies of 46.18 ± 0.32% (GABA) and 82.01 ± 1.33% (Nar), respectively. The stability of GABA‐Nar‐Lip was significantly enhanced after lyophilization with sugars (especially 0.10 g mL −1 trehalose) as cryoprotectants (CPAs), and maintained targeted release in the small intestine. The CPAs exerted cryoprotective effects by replacing water molecules and forming hydrogen bonds with soy phosphatidylcholine, thereby preserving the spherical structure and unilamellar vesicle morphology of the liposomes. In caffeine‐induced zebrafish models, lyophilized GABA‐Nar‐Lip showed an inferior but still significant effect in sleep latency reduction. Moreover, it decreased nocturnal twitching activity and enhanced daytime locomotor activity on the following day, without the adverse effects associated with melatonin, such as poor sleep quality and reduced daytime activity. CONCLUSION The stabilized lyophilized GABA‐Nar‐Lip powder is a promising, safe sleep aid with balanced efficacy and no compromise to next‐day performance, supporting its potential application in dietary sleep interventions. © 2026 Society of Chemical Industry.