J Control Release. 2026 Jul 6:115162. doi: 10.1016/j.jconrel.2026.115162. Online ahead of print.

ABSTRACT

Current gastroesophageal reflux disease (GERD) therapies either systemically suppress gastric acid, risking physiological disruption, or rely on antacid rafts that offer transient, non-responsive neutralization. We address this with a chemistry-centered strategy that spatially localizes proton conversion around the self-positioning raft at the gastric interface. The dynamic H⁺ conversion equilibrium system (DH⁺-CES) integrates a CO₂-generating calcium alginate raft which physically impedes reflux via its bubble-stabilized architecture for rapid interfacial self-positioning, with an engineered Lactococcus lactis expressing acid urease. Under acidic challenge, urease catalysis consumes protons locally. As pH normalizes, feedback-regulated enzymatic attenuation constrains the reaction zone, preventing bulk alkalization. DH⁺-CES elevates interfacial pH from 2.0 to ~5.0 within 5 min, sustains this zone for hours while modulating only 5.38% of total fluid volume, and reduces reflux-like surge height by 38%. In an acute rat GERD model, it inhibits esophageal injury by 93.95%, downregulates key inflammatory mediators, and shows favorable biocompatibility. These findings establish DH⁺-CES as a proof-of-concept interface-resident chemical gatekeeper for localized, self-limiting, and physiologically respectful pH control.

PMID:42409243 | DOI:10.1016/j.jconrel.2026.115162