A Mechanism-Guided Delivery System for Long-Acting Postpartum Depression Therapy via Hydrogen-Facilitated Gut Microbiota Reprogramming.

To address the limitations of current pharmacotherapies for postpartum depression (PPD), this study developed an innovative oral delivery system (EL@HRG) based on calcium-cross-linked alginate/WPI emulsion nanogel particles, leveraging the mechanism reported in Cell where in hydrogen (H2) drives the gut commensal bacterium Eggerthella lenta to convert host corticosterone into the neuroactive steroid allopregnanolone. The core innovation of this work lies in the of a controlled hydrogen-release carrier with a probiotic delivery platform into a unified system. Using a scaffold of sodium alginate and whey protein integrated with corn oil to form an emulsion, we leveraged the higher solubility of H2 in the oil phase to overcome the key bottleneck of maintaining effective intestinal hydrogen concentration after oral administration. Concurrently, l-arginine, an essential nutrient for E. lenta growth, was incorporated into the gel network, achieving an integrated "delivery-colonization-activation" function. In vitro experiments confirmed that EL@HRG provided sustained hydrogen release and efficiently encapsulated viable bacteria. In vivo studies demonstrated that EL@HRG significantly enhanced the intestinal colonization and retention of E. lenta, leading to sustained activation of the steroid conversion pathway and elevated levels of allopregnanolone in the brain. In a PPD mouse model, EL@HRG, acting via the gut-brain axis, inhibited hippocampal neuroinflammation, restored synaptic plasticity and GABAergic signaling, and consequently markedly improved depressive-like behaviors, anxiety, and maternal behavior deficits. Its therapeutic efficacy showed enhanced sustainability compared to the short-term effects of injected allopregnanolone, with no observed systemic toxicity. Metabolomic analysis further revealed a reshaping of the "steroid hormone biosynthesis" pathway, underpinning the therapeutic effect. In conclusion, this study provides a novel, nonpharmacological, long-acting, and safe interventional strategy for PPD. It also establishes a new paradigm of mechanism-guided delivery systems for precisely modulating the gut microenvironment to achieve specific physiological functions.