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.