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

Mesoporous silica nanoparticles (mSiO 2 –NPs) are efficient drug delivery vehicles, yet their surface chemistry critically dictates payload uptake, therapeutic efficiency, and biocompatibility. Conventional organic coatings on the surface, such as polyethylenimine (PEI), improve drug loading capacity but substantiate cytotoxicity, while inorganic coatings/surface functionalization (e.g., (3-aminopropyl)trimethoxysilane (APTMS)) grafting reduces toxicity but offers uncontrolled drug release. Here, we present the first systematic comparison of APTMS- and PEI-functionalized mSiO 2, 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.