Dual-Targeted Nanotherapy Restores Redox Homeostasis and Suppresses Uterine Hypercontractility for Effective Preterm Birth Intervention.

Preterm birth (PTB), defined as delivery between 28 and 37 weeks of gestation, is a leading cause of global neonatal mortality. Its pathogenesis is primarily driven by oxidative stress and inflammation, synergistically inducing calcium ion influx into uterine smooth muscle cells, triggering aberrant contractions and PTB. Current therapies primarily offer only symptom suppression without addressing the underlying etiology, highlighting an urgent need for targeted interventions. Herein, we develop TPT, a multi-bioactive, amphiphilic conjugate, which is synthesized through stepwise covalent conjugation of hydrophilic polyethylene glycol, a superoxide dismutase mimetic, and a hydrogen peroxide-scavenging/anti-inflammatory generating unit onto a molecular skeleton. TPT can self-assemble into a multifunctional nanotherapy (designated as TPT NP). In both in vitro and in vivo lipopolysaccharide-induced PTB models, TPT NP treatment significantly mitigates oxidative/inflammatory cascades, reduces calcium influx and apoptosis in uterine smooth muscle cells, and suppresses myometrial contractions, thereby effectively delaying PTB. Mechanistically, TPT NP restores redox homeostasis in lipopolysaccharide-induced PTB by reducing oxidative damage products and bolstering endogenous antioxidant defenses, while concurrently improving uteroplacental hemodynamics and attenuating uterine hypercontractility. Critically, in vivo evaluations demonstrate excellent safety profiles of TPT NP, with no adverse effects on maternal health and offspring development, underscoring its significant clinical translational potential.