Orchestrating membranous biomaterials preservation: multi-pathway immunomodulation of macrophage fusion and membrane stability via BAPTA-loaded mesoporous silica nanoparticles

Membranous biomaterials play a vital role in regenerative medicine by maintaining barrier function and guiding tissue repair, but their clinical efficacy is often limited by premature degradation driven by host immune responses, particularly macrophage fusion. Addressing this challenge, we developed a delivery platform based on mesoporous silica nanoparticles loaded with a cell-permeable calcium chelator (BAPTA), which were uniformly spray-coated onto collagen membranes for precise control of coating thickness. In vitro, these coating ingredients were highly biocompatible, efficiently internalized by macrophages, and effectively attenuated IL4-associated cytosolic Ca2+ elevation and phosphatidylserine externalization, thereby blocking cell fusion initiation. Transcriptomic analysis showed upregulation of cytomembrane-stabilizing and cytoskeletal pathways (Rap1, PI3K-Akt, focal adhesion, ECM-receptor interaction), and downregulation of apoptosis and pro-fusion pathways. In a rat subcutaneous implantation model, BAPTA-coated membranes exhibited a thickness-dependent reduction in multinucleated giant cell formation and delayed membrane degradation, without systemic toxicity. Overall, this study demonstrates that targeted modulation of intracellular calcium signaling and multi-pathway immunoregulation can inhibit macrophage fusion, stabilize cytomembrane-cytoskeleton interactions, and prolong membrane function. This host-targeted approach offers a safe and effective strategy for enhancing the durability of regenerative biomaterials via a designed immunomodulatory interface, and may inform the rational design of next-generation membranes in tissue engineering.