Abstract: Phospholipid-conjugated Ags were used as an agnostic delivery platform to cell type, activation state, and inherent uptake capabilities for engineering APCs to control Ag-specific cellular immune responses. Lipid-mediated delivery (termed depoting) of MHC class I and II-restricted Ags successfully loaded resting polyclonal B cells, CD40? activated B cells, and DCs in a dose-dependent manner for priming Ag-specific CD8+ and CD4+ T cells, respectively. When lipid-conjugated Ags were paired with polymer-conjugated Ags and incorporated in nanoparticles (NPs), diverse APCs with varying NP internalization capabilities all processed the lipid-conjugated Ags via depoting while only DCs processed the PLGA-conjugated Ags via endocytosis. Multivariate analyses of cytokine secretions indicated that lipid-conjugated Ags could be distinctly classified from polymer-conjugated Ags.