Electrostatic Remodeling of the Plasma Membrane Enables Caveolae-Mediated ZIF8 Delivery for Bone Regeneration
Shuting Gao, Yayuan Zheng, Zhihao Dou, Xiupei Yin, Yumin Wang, Jian Su, Keyu Tang, Qiaozhen Zhou, Kangli Jiao, Baoping Zhang, Ziyan Nie, Kailiang ZhangAbstract
Metal–organic frameworks offer powerful platforms for intracellular delivery and tissue regeneration, yet their membrane-level interactions are poorly defined. Here, we show that cationic zeolitic imidazolate framework-8 (ZIF8) remodels the electrostatic landscape of the anionic plasma membrane, triggering caveolae-dependent endocytosis and promoting the intracellular delivery for bone regeneration. ζ-potential analysis and Kelvin probe force microscopy demonstrated that ZIF8 rapidly increased membrane surface electrostatics and induced localized electrostatic polarization at the nanobio interface. Simulations and adsorption kinetics revealed rapid saturation and a strong pH dependence, supporting a charge-dominated adsorption mechanism. Transmission electron microscopy captured sequential uptake events, including caveolae formation, membrane invagination, and lysosomal trafficking. Transcriptomics further identified CAV2-associated endocytosis and mechanosensitive fluid shear-stress pathways as key contributors. On the basis of this mechanism, we constructed an OGP-loaded ZIF8 coating on polyethyleneimine-functionalized titanium implants, enabling intracellular peptide delivery, partial lysosomal escape, enhanced osteogenesis, antioxidant and anti-inflammatory responses, and improved osseointegration in rat bone defect models.