Bioadhesive Hydrogel with CO ₂ ‐Induced Water Repulsion and Tissue Anchoring for Drug Delivery and Wound Management

Abstract Tissue interfacial water critically hinders adhesion and therapeutic efficacy of bioadhesives. Herein, a simple yet versatile strategy is proposed to repel interfacial water by in situ generated carbon dioxide (CO 2 ) bubbles, which can promote tight hydrogel‐tissue interface anchoring and bioadhesion. By spraying sodium bicarbonate (NaHCO 3 ) solution onto the polyvinyl pyrrolidone/gallic acid/citric acid (PVP/GA/CA) hydrogel and pressing it onto the wet tissue, numerous CO 2 bubbles generated in situ repel interfacial water, achieving tight hydrogel‐tissue interface anchoring. Meanwhile, the functional groups between the hydrogel and tissue form covalent and non‐covalent bonds to induce strong bioadhesion, showing an adhesion strength of 44.5 kPa. This tight hydrogel‐tissue interfacial anchoring enables efficient delivery of GA and epidermal growth factor from the hydrogel to the wound site. In infected rat skin wounds, the NaHCO 3 ‐hydrogel outperformed commercial gel with 16.6 fold lower bacterial density, 42.8 fold fewer M1 macrophages and 43.8 fold more M2 macrophages, 4.7 fold higher platelet endothelial cell adhesion molecule‐1 (CD31) density, and 3.3 fold more proliferating cell nuclear antigen (PCNA) cells. RNA sequencing further validated its wound healing mechanism, including suppressing inflammation and reconstructing the extracellular matrix. Due to its strong bioadhesion, antibacterial and anti‐inflammatory properties, drug delivery, and biocompatibility, this NaHCO 3 ‐treated PVP/GA/CA hydrogel is an ideal bioadhesive for biomedical applications, such as sealants, wearable devices, and drug delivery.