Interfacial Bioengineering of Dynamic Networks Hybrid Hydrogel for Programmed Intervention in Oral Precancerous Epithelial States

ABSTRACT A major challenge in precision medicine is the development of advanced biomaterials for targeted intervention in precancerous states. Here, we introduce an interfacial bioengineering strategy to construct a dynamic network for programmed intervention in epithelial precancerous lesions. Our dual‐bioinspired hydrogel, MSA@PGel (macrophage membrane‐coated and salvianolic acid B [SAB] /5‐aminolevulinic acid co‐loaded liposomes embedded in a polydopamine‐based gel), leverages both the powerful wet adhesion of mussels and the immune‐targeting capabilities of macrophages. The material's core innovation lies in its dynamic catecholato‐Fe 3+ coordination bonds, which form a robust network with a storage modulus (G′) exceeding 8.8 kPa higher than that of the base hydrogel (G′ > 2.2 kPa), thereby demonstrating superior mechanical properties and exceptional mucosal adhesion. This system achieves unprecedented lesion‐specific delivery by functionalizing the network with macrophage membranes to exploit VCAM‐1 overexpression in dysplastic epithelium, thereby overcoming the “mucosal delivery barrier” and ensuring prolonged retention (>3 h). The programmed intervention specifically targets HIF‐1α, a metabolic regulator of malignant transformation. Through SAB‐mediated HIF‐1α sequestration, our dynamic network not only effectively disrupts hypoxia adaptation to enhance phototherapy but also triggers a significant apoptotic cascade. In vivo studies confirm significant histological normalization, a significant increase in ROS generation, and excellent biosafety. This work establishes a versatile interfacial bioengineering platform, pioneering a new paradigm for the programmed management of epithelial precancerous states through the synergistic integration of biomaterial design and disease‐specific targeting.