Immunization with peptide encapsulated within synthetic spores activates T cell responses and reduces tumor growth.

Peptide-based therapeutic immunizations represent safe approaches to elicit antigen-specific T cell responses, but their broad utility remains limited due to poor immunogenicity and short in vivo stability due to rapid degradation and clearance. Here, we employed synthetic bacterial spore-like particles, "SSHELs" (Synthetic Spore Husk-Encased Lipid), made entirely of biocompatible materials, to deliver a model peptide antigen in the absence of additional adjuvants. SSHELs carrying the peptide antigen were internalized by dendritic cells, and SSHEL-delivered peptides were then processed and cross-presented in vitro and in vivo more efficiently than free peptides. Furthermore, SSHEL-delivered peptides elicited effective antigen-specific T cell expansion in a manner that was dependent on particle size and peptide presentation mode (encased peptides were superior to surface-attached peptides). In a mouse melanoma model expressing the antigen ovalbumin, therapeutic immunization reduced tumor size and increased survival. We propose that SSHELs are a self-adjuvanting peptide delivery system that mimics a natural presentation to elicit a robust immune response.IMPORTANCEEffective delivery of antigens to the immune system is essential for activating the adaptive immune system. Synthetic Spore Husk-Encased Lipids (SSHELs) are synthetic bacterial spore-like particles, where the proteinaceous polymerized surface layer of Bacillus subtilis spores is partially reconstituted around a porous silica bead encased in a membrane. The protein surface allows easy covalent modification of the SSHEL surface, and the porous core permits high-capacity cargo loading. Here, we demonstrate that SSHELs act as a self-adjuvanting delivery system that enhances antigen uptake, processing, and MHC-I cross-presentation by dendritic cells. Importantly, we show that both particle size and antigen localization on or within the SSHEL particle profoundly influence the efficiency of T cell priming. These results establish SSHELs as a modular platform for the delivery of peptide antigens.