Biointerface engineering of cellulose nanofibers to design immunomodulatory Pickering emulsion microparticles

Cellulose nanofiber (CNF)-stabilized Pickering emulsions (PEs) with preferable biocompatibility and designable functionality have been widely applied in foods, biomedicine, and cosmetics in recent years. However, their cellular uptake behavior and immune responses remain poorly understood. Herein, we investigate how surface modifications of CNFs, specifically phosphorylation, sulfation, and carboxylation, affect their emulsifying performance and subsequent interactions with fibroblasts, hepatocytes, Kupffer cells, and macrophages. All types of PE microparticles induced lactate dehydrogenase release and pyroptotic cell death in these cells, except in monocytes. Notably, sulfated CNF-stabilized PEs (SPEs) with droplets sizes around 1 μm exhibited long-term stability (up to 2 months) and the highest antigen-loading capability. Although SPEs triggered lysosome damage and reactive oxygen species (ROS) in Kupffer cells, they significantly downregulated the gene expression of inflammatory cytokines (interleukin-6, interferon, and tumor necrosis factor) in macrophages. By selecting appropriate surface functional groups on CNFs and tailoring a flexible glyco-endowed oil–water interface, immune stimulation can be effectively modulated. This work offers a strategy for designing cellulose-based immunomodulatory microparticles with potential applications in anticancer therapeutics and vaccine adjuvants. • Surface-functionalized CNFs contributed to the excellent stability, tunable size, and high antigen-loading capacity of Pickering emulsions. • Sulfated CNF-stabilized PE (SPE) exhibited remarkable stability under various environmental conditions for at least 60 days. • SPE induced cell-type-specific differential immune responses, including pro-death effects in cancer cells while keeping anti-inflammatory effects in macrophages. • This biointerface engineering strategy transforms bioinert cellulose into bioactive microparticles, providing a promising medical modality for immunomodulators.