Microspheres (MS; 1-3 μm) with different degrees of surface roughness were prepared to assess the effects of surface topology on internalization into antigen-presenting cells (APCs; macrophages and dendritic cells). In this study, we demonstrated that the intracellular uptake of MS is readily enhanced by surface modification with nanoparticles or cancer cell-derived vesicles (VE) to modulate their surface topology. MS coated with nanovesicles (MS-VE) with high surface roughness was more successfully and efficiently engulfed by APCs, compared with bare MS and those with low surface roughness. Incorporated MPLA within MS-VEs (M/MS-VE) triggered greatly elevated release of immune stimulating cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), from macrophages and dendritic cells, compared to free MPLA. Taken together, this MS-VE could serve as a platform system for the delivery of immune stimulators and antigens to APCs with negligible toxicity.