Mannose-Conjugation Resolves the Efficiency–Toxicity Trade-Off in Amine Functionalized Silica Nanocarriers via Tunable pH-Responsive Drug Release

, with and without mannose conjugation, to establish how sequential surface modification governs nicotinic acid (NA) loading, release kinetics, and cellular response. Using NA as a model drug, PEI-coated carriers achieved the highest loading (DEE = 83%) and sustained, pH-responsive release (41% in 24 h at pH 5.5) but displayed pronounced cytotoxicity in breast cancer cells (MCF-7) and peripheral blood mononuclear cells (PBMCs). Mannose conjugation substantially reduced this toxicity, while maintaining drug loading efficiency and enhancing cellular uptake in both epithelial and immune cell cultures. Notably, mannose-functionalized PEI carriers exhibited targeted, stimulus-sensitive release and selective enrichment in monocyte subsets without inducing immune activation, consistent with uptake mediated by carbohydrate-binding receptors confirmed via confocal colocalization analysis. These findings establish mannose coating as an effective strategy to reconcile efficiency and safety in amine-functionalized silica nanocarriers, providing a practical design principle for targeted and biocompatible drug delivery systems.