Glucan particles (GPs) are hollow, porous 3–5 µm microspheres derived from the cell walls of Baker’s yeast (Saccharomyces cerevisiae). Their 1,3-β-glucan outer shell allows for receptor-mediated uptake by macrophages and other phagocytic innate immune cells expressing β-glucan receptors. GPs have been used for the targeted delivery of a wide range of payloads, including vaccines and nanoparticles, encapsulated inside the hollow cavity of GPs. In this paper, we describe the methods to prepare GP-encapsulated nickel nanoparticles (GP-Ni) for the binding of histidine (His)-tagged proteins. His-tagged Cda2 cryptococcal antigens were used as payloads to demonstrate the efficacy of this new GP vaccine encapsulation approach. The GP-Ni-Cda2 vaccine was shown to be comparable to our previous approach utilizing mouse serum albumin (MSA) and yeast RNA trapping of Cda2 in GPs in a mouse infection model. This novel GP-Ni approach allows for the one-step binding of His-tagged vaccine antigens and encapsulation in an effective delivery vehicle to target vaccines to antigen-presenting cells (APCs), antigen discovery, and vaccine development.